HU189545B - Process for producing 2-oxo-azetidine derivatives - Google Patents

Abstract

1-Sulfo-2-oxoazetidine derivatives of the general formula (I) …<CHEM>… wherein R1 is amino group which may optionally be acyiated or protected, X is hydrogen or methoxy, and R4 is azido, a halogen, amino group which may optionally be acylated or a group of the formula -OR5, …<CHEM>… or -S-S-R5 in which R5 is an organic residue and n is 0, 1 or 2, or a pharmaceutically acceptable salt thereof, or an ester thereof as well as methods of production in accordance with the following schemes: …<CHEM>… wherein R2 is an acylated or protected amino group, R3 is an acylated amino group, and R1 and R4 are as above defined. The compounds [I] have antimicrobial and beta -lactamase inhibitory activity.

Description

This invention relates to novel 2-oxoazetidine derivatives. More particularly, the present invention relates to the preparation of novel 1-sulfo-3,4-disubstituted-2-oxoazetidine derivatives and their pharmaceutically acceptable salts having antimicrobial or β-lactamase inhibitory activity.

Many different 2-oxoazetidine derivatives have been prepared in recent years. Annalene Derry Chemie 1974, 539 by reacting a vinyl ester with chlorosulfonyl isocyanate to form 4-acetoxy-2-oxoazetidine derivatives which can then be subjected to a nucleophilic substitution reaction at the 4-position with a benzoyloxy, alkylthio or or other similar group. This process seems to involve the formation of a compound having a chlorosulfonyl group at the 1-position, but since the chlorosulfonyl group is highly prone to cleavage, the corresponding intermediate is not easily isolated. Examples of the compounds discussed in the literature are 3-methyl-4-acetoxy-2-oxoazetidinone. These compounds have been shown to have very weak antimicrobial activity.

In our experiments with the preparation of new and useful azetidine derivatives, we have discovered that azetidine derivatives bearing a sulfone group in the 1-position are suitable for the above mentioned purpose. Thus further experiments it recognized result to the azetidine derivatives of general formula (I) - wherein X ³⁵ is hydrogen or methoxy,

R ₄ is (1) azido, (2) halo, (3) a group of formula VIII, ⁴⁰ in which Rj is

A cycloalkyl group containing from 4 to 8 carbon atoms,

C 1-6 alkyl optionally with (a) an alkoxycarbonyl group containing from 1 to 4 carbon atoms in the alkyl moiety, or a alkanoyl group with ⁴⁵ (b) optionally formyl, p-nitrobenzyloxycarbonyl or alkyl moiety in the alkyl moiety; can be substituted with a substituted amino group,

Alkylthio of 1-4 carbon atoms ⁵⁰ substituted thiocarbonyl group, optionally substituted alkanoylamino group having 1-4 carbon atoms in the substituted alkenyl group, a phenyl group, ⁵⁵ 6 1- (1-4C) alkyl-lH-tetrazolyl group, having 2-4 carbon atoms or the alkyl moiety contains an alkanoyl group containing from 1 to 4 carbon atoms and n is 0, 1 or 2, (4) a group of formula VII wherein R ₅ is optionally substituted by an alkoxycarbonyl group containing from 1 to 4 carbon atoms in the alkyl moiety; Alkyl having 4 carbon atoms, or

2 optionally substituted by phenyl, the alkyl part 545 .189 alkanoyl group having 1-4 carbon atoms, or (5) a (X) a group of formula in which R _s represents benzothiazolyl and

R 1 is (1) a group of formula XI wherein R _e is isoxazolyl optionally substituted with 2.6 dichlorophenyl or C 1 -C 4 alkyl, (2) a group of formula XII in which wherein R ₇ is a group of formula (XIII) (wherein R ₈ is a group of formula (XXXV) wherein A 'is C 1 -C 4 alkyl or C 4 -C 8 cycloalkyl or XXXVI) - wherein A is hydrogen or sulfo or thiophene-3-aldoimido - or a group of formula XIV wherein R 1 and R 8 are independently hydrogen or C 1 -C 4 alkyl, the alkyl moiety being 1 to 4 carbon atoms are alkylcarbamoyl or sulfo groups - and

R _o is an optionally substituted alkynyl group or a halogen, hydroxy, formyloxy or 2-4 carbon atoms, alkyl, phenyl, thienyl, 'benzothiophenyl or an amino-thiazolyl group, (3) a (XVI) with a group of formula C 1-4 alkyl, wherein R ₁₀ is a group of Formula XVII and the latter

R 2 is a thiazolyl group optionally substituted with amino, haloacetamido, sulfoamino, formamido, tritylamino or alkylthio (C 1-4) alkylcarboxamido, and

R, alkyl containing 1-6 carbon atoms R 3 represents a group of formula ₁₅ R _I4, which latter _{R) S} and R is alkylene containing _four carboxy of 1-6 carbons, optionally substituted with a tri (1-4C) alkyl silyl-substituted alkoxycarbonyl or tetrazolyl (C1-4alkyl) means (4), (XIX) wherein, in the formula, R ₁₇ is halogen, (5) formula (XX) wherein, in this formula R _{e is} phenyl, phenoxy or thienyl, (6) 2 - ([2- (trityl-amino- or amino) -thiazol-4-yl] -carboxymethyliminoxy) -2-methyl-propionamido, (7) benzyloxycarboxamido, p-nitrobenzyloxycarboxamido, or 2- [tri (C 1 -C 4) alkylsilyl] ethoxycarboxamide, or (8) amino, and their pharmaceutically acceptable salts are highly valuable antimicrobial and β- they have lactamase inhibitory activity,

The compounds of formula (I) and their pharmaceutically acceptable salts are prepared according to the invention by:

a) a compound of formula II wherein X and R ₄ are as defined for formula I and R ₂ is one of the acylated amino groups represented by numbers (1) to (7) above - or a salt thereof or a 1-silyl group; the derivative thereof is sulfonated and optionally, when R _{2 is} acylated amino, the acyl group is cleaved, or

b) R, in place of the above (1) - numbered (7) are acylated-amino (I) Compounds of formula I, i.e. compounds of formula (IV): - wherein X and R ₄ are as defined above and R ₃ represents equivalent to R as defined in report - preparation of (III) a compound of the formula: - wherein X and R ₄ are as defined in formula (I) - is acylated with an acylating agent containing the acylamino numbered (7) are one of, and - acyl group of the above (1) optionally converting the compound of formula (1) obtained by process a) or b) into a pharmaceutically acceptable salt.

When used as an active ingredient, the compounds of formula (I) according to the invention can be formulated into pharmaceutical compositions having antimicrobial or β-lactamase inhibiting activity according to the invention.

In the formula (XIV), the alkyl groups preferably have from 1 to 3 carbon atoms in the form of R _g and / or R j. The alkyl portion of the alkylcarbamoyl group preferably also contains from 1 to 3 carbon atoms.

In Rg, optionally substituted alkyl preferably contains from 1 to 3 carbon atoms.

The alkylene group in R ₁₄ is preferably 1 to 3 carbon atoms and is, for example, methylene, ethylene, dimethylethylene, methylethylene or ethylmethylene.

Examples of the esterification groups of the esterified carboxyl group in R ₁₅ include methyl, ethyl, propyl, tert-butyl, and 2- (trimethylsilyl) ethyl.

Examples of C 1-6 -alkyl include methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl. and isohexyl.

The halogen atom mentioned in the above-mentioned substituent meanings may be fluorine, chlorine, bromine or iodine.

An example of a compound of formula (XI) is 3- (2,6-dichlorophenyl) -5-methylisoxazol-4-ylcarbonyl.

Exemplary groups of formula XII include 2- (2-aminothiazol-4-yl) -2- (4-ethyl-2,3-dioxo-piperazinecarboxamido) -acetyl, 2- (4-ethyl). -2,3díoxo-l-piperazinocarboxamido) -2-thienylacetyl,

D-2- (4-cyclohexyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetyl, D-2- (4-cyclohexyl-2,3-dioxolepiperazinecarboxamido) -2 -thienylacetyl, N- (4-ethyl-2,3-dioxo-1-piperazinecarbonyl) -D-alanyl, 2} [(2-oxo-3- (thiophene-2-aldimino) imidazolidine-1) -yl] carboxamido} -2-phenylacetyl, 2 - {[2-oxo-3- (thiophene-2aldimino) imidazolidin-1-yl] carboxamido} -2-thienylacetyl, D-3- ((2-oxo-3-sulfoimidazolidin-1-yl) carboxamido] -2-thienylacetyl, 2-ureido-2-thienyl3

189,545 acetyl, Ν-carbamoyl-D-phenylglycyl, 2- (3-methylcarbamoyl-3-methyl-1-ureido) -2-phenylacetyl, 2- (3-methylcarbamoyl-3-methyl- 1 -ureido) -2-thienylacetyl, 2- (2-aminothiazol-4-yl) -2-ureidoacetyl, 2- (2-aminothiazol-4-yl) -2- ( 3-methyl-1-ureido) acetyl, D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S) formyloxy butyryl or D-2- (4- ethyl-2,3-dioxo-l-piperazinecarbonyl-carboxamido) -3- (S) -hydroxy-butyryl.

Exemplary groups of formula (XVI) include 2- (2-chloroacetamidothiazol-4-yl) -2- [2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetamido]. -acetyl, 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetyl, 2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetyl, 2- (2-amino-thiazol-4-yl) -2-methoxyiminoacetyl, 2- (2-amino-thiazol-4-yl) -2- (carboxy-1-methyl-ethoxyimino) -acetyl, 2- [1- (tert-butoxycarbonyl) -1-methylethoxyimino] -2- (2-sulfoaminothiazol-4-yl) acetyl, 2- [1- (tert-butoxycarbonyl) - 1-Methyl-ethoxyimino] -2- (2-triphenylmethyl-aminothiazol-4-yl) -acetyl, 2- (2-chloro-acetamidothiazol-4-yl) -2- (1-methyl- ethoxyimino) acetyl, 2- (methoxyimino) -2 (2-hydroxysulfonylaminothiazol-4-yl) acetyl, 2- (2-methylaminothiazol-4-yl) - 2- (l-methyl-ethoxyimino) acetyl, 2- (2-aminothiazol-4-yl) -2 - [(carboxy) ^methoxy: imino] acetyl, 2- [2-amino- thiazol-4-yl] -2 - ((1-carboxyethoxy) imino] acetyl, 2- (2-chloroacetamido-thiazol4-yl) -2- [1- (2-trimethylsilyl) ethoxycarbonyl) -1- (methylethoxy) imino] acetyl, 2- [1- (2-Trimethyl-1-silyl-ethoxycarbonyl) -1- (methoxy-ethoxy) -amino] -2- (2-trityl-amino-azol-4-yl) -acetyl-2- (2-amino- thiazol-4-yl) -2 - [(1-methoxycarbonyl-1-methyl) -ethoxyimino] -acetyl, 2- (2-amino-thiazol-4-yl) -2 - [(carbamoyl) -methoxy- imino] acetyl, 2- (2-aminothiazol-4-yl) -2 - [(tetrazol-5-yl) methoxyimino] acetyl or 2- (2-aminothiazol-4-yl) - 2 [methoxycarbonylmethoxyimino] acetyl.

Exemplary groups of formula (XIX) include 2-bromo-2-phenylacetylamino.

Exemplary groups of general formula (XX) include phenylacetylamino, phenoxyacetylamino or 2-thienylacetylamino.

In the case of starting materials, the amino and / or carboxyl groups of the acyl groups may be protected.

Protecting groups for said amino group include those which will be listed below.

The protecting group of said carboxyl group may be any group used to protect the carboxyl group in organic or β-lactam compounds. For example, the esterification groups of the corresponding ester groups include methyl, ethyl, propyl, isopropyl, tert-butyl, tert-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, phenacyl. , phenyl, ρ-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, pivaloyloxymethyl, t-methylsulfonylethyl, methylthio. methyl, trityl, β, β, β-trichloroethyl, N-iodoethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 2- (trimethylsilyl) ethyl -, 2-cyanoethyl, trimethylsilyl, dimethylsilyl, acetylmethyl, ρ-nitrobenzoylmethyl, p-methylbenzoylmethyl, phthalimidomethyl, propionyloxymethyl, 1, 1-dimethylpropyl, 3-methyl-3-butenyl, succinimidomethyl, 3,5-di-tert-butyl-4-hydroxybenzyl, mesylmethyl, benzenesulfonylmethyl, phenylthiomethyl, dimethylaminoethyl, pyridine-1-oxido-2-methyl, methylsulfinylmethyl, bis (p-methoxyphenyl) methyl or 2-ciaηο-Ι, dimet-dimethyl.

Benzyl, 2,2,2-trichloroethyl, 2- (trimethylsilyl) ethyl, benzhydryl, tert-butyl, 4-nitrobenzyl and 4-methoxybenzyl are particularly preferred.

The amino protecting groups present in the above formulas and groups may be those commonly used in the chemistry of lactam compounds and peptide synthesis. Examples of such groups are aromatic acyl groups such as phthaloyl, 4-nitrobenzoyl, 4- (tert-butyl) benzoyl, 4- (tert-butyl) benzenesulfonyl, benzenesulfonyl or toluenesulfonyl; aliphatic acyl groups such as formyl, acetyl, propionyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, malonyl, succinyl, benzyloxycarbonyl -, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl or methoxycarbonyl, and non-acyl-type amino protecting groups such as trityl, 2-nitrophenylthio, benzylidene,

4-nitrobenzylidene, di- or trialkylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyl or 4-nitrobenzyl. The nature of the protecting group used in the particular case, like the carboxy protecting group, is not important. However, we particularly prefer monochloroacetyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl and the like.

4-nitrobenzyloxycarbonyl groups.

Because they carry a sulfo group, the compounds of formula (I) generally form salts with bases. Therefore, the compounds of formula (I) may be isolated as their salts or the products isolated as the salt may be converted to the corresponding free acids or converted to another salt. Further, the compounds of formula (1) obtained in the form of the free acid can be converted into salts. Bases used for salt formation include inorganic bases such as lithium, potassium, sodium and calcium and ammonia as well as organic bases such as pyridine, collidine, triethylamine, tetra-n-butylammonium hydroxide or the like. triethanolamine.

Salts of the compounds of formula I can be converted into the free acid, for example, by treatment with an acid. The nature of the acids used for this purpose will depend on the nature of the protecting groups and other factors, but inorganic acids such as hydrochloric, sulfuric or phosphoric acid, and organic acids such as formic acid, acetic acid or p-toluenesulfonic acid are usually used. Acid ion-exchange resins can also be used for this purpose. Of the solvents, hydrophilic organic solvents, such as acetone, tetrahydrofuran, methanol, ethanol and dioxane, as well as water and mixtures thereof, are the most commonly used solvents.

Depending on the circumstances, the compounds of formula I may be derived from stereoisomers (e.g., D and

189,545

L-isomers). Of course, both individual isomers and mixtures of isomers are contemplated to be within the scope of the invention.

Not only the individual isomers, but also mixtures thereof may be used in the preparation of pharmaceutical compositions. When a mixture of such isomers is obtained as a product, the individual isomers are separated by methods well known in the art for optical resolution.

As mentioned above, the compounds of formula (I) can be used as active ingredients in pharmaceuticals, for example, because of their antibacterial activity against certain Gram-positive and Gram-negative bacteria.

As regards the acute toxicity of the compounds of formula (I), intravenous LD _S0 value, measured in mice 500 mg / kg or greater.

The compounds of the formula I can be used, for example, in the treatment of mammals (e.g., mice, rats or humans) infected with the bacteria mentioned above.

The compounds of formula (I) are thus useful in the treatment of, inter alia, bacterial infections, respiratory tract infections, urinary tract infections, purulent diseases, infectious epetractic disease, gastrointestinal infectious and in case of. The daily amount of the compounds of formula (I) may be from about 20 to 200 mg / kg body weight, administered in divided doses 2 to 4 mg / kg body weight, once daily. The compounds of formula (I) or pharmaceutically acceptable salts thereof may be administered, for example, orally, in the form of tablets, capsules, or lozenges. They may also be administered parenterally in the form of injectable formulations prepared with conventional carriers.

The compounds of formula (I) are / are inhibitors of lactamase and can thus be used / as lactamase inhibitors.

The compounds of formula (I) are thus useful in the administration of lactam-type antibiotics to humans or animals for the prevention or treatment of bacterial infections.

When the compounds of formula (I) are formulated on their own into pharmaceutical compositions, these pharmaceutical compositions may be administered before or after administration of the? -Lactam antibiotic, or may be mixed with the? -Lactam antibiotic prior to administration. Alternatively, the compounds of formula (I) may be formulated into a pharmaceutical composition in admixture with a / lactam antibiotic. In the latter case, for example, antibiotics such as benzyl-penicillin, phenoxymethyl-penicillin, sulbenicillin, carbenicillin, ampicillin, amoxicillin, mecithlin, cloxacillin, dicloxacillin, piperacillin, cephalothin, cefazolin, cephalexin, cefacetrile, cefamandolenaftate, cefuroxime, cefmelazole, cefsulodine, cefaclor, cefatrizine, cefotaxime, cefmenoxime, ceftadizine, ceftezime and ceftezime derivative , talampicillin, carindacillin, carfecillin and pivmecillin. These pharmaceutical compositions containing the two active ingredients may be prepared, for example, by injection, anhydrous syrup, granules, tablets or capsules, in the usual manner. Preferably, however, the active compounds are used in the form of their salts or hydrates in the form of injectable formulations. In such cases, the compound of formula (I) is used in an amount of 0.1 to 10 parts by weight, preferably 1: 1 to 1: 8, for example 1: 5 or 1: 6, based on 1 part by weight of a lactam antibiotic. Generally, the compounds of the formula I are administered in an amount of 50 to 1000 mg per day, more usually in a dosage of 20 to 150 mg / kg body weight per day, in 1 to 6 doses, usually 2 to 4 doses.

The 1-sulfo-2-oxoazetidine derivatives of the formula (I) according to the invention may be prepared by sulfonating a compound of the formula (II). This sulfonation reaction is a reaction suitable for introducing a sulfo group. In the process, a compound of formula II is treated with sulfur trioxide or a reactive derivative thereof.

As the reactive derivative of sulfur trioxide, for example, the sulfur trioxide adduct with N, N-dimethylformamide, pyridine, dioxane, trimethylamine or chlorosulfonic acid can be used.

In the reaction, sulfur trioxide or one of its reactive derivatives is used in an amount of about 1 to 5 moles, preferably 1 to 2 moles, per mole of the compound of formula II.

The reaction temperature is about 0-80 ° C, preferably 10-40 ° C. The reaction may be carried out with a solvent. Suitable solvents for this purpose include ethers such as dioxane, tetrahydrofuran or diethyl ether; esters such as. ethyl acetate or ethyl formic acid; halogenated hydrocarbons such as chloroform or methylene chloride; hydrocarbons such as benzene, toluene or n-hexane; amides, such as dimethylformamide or dimethylacetamide, and other conventional organic solvents or mixtures thereof. Following the reaction, the product of formula I can be isolated in any purity by subjecting the reaction mixture to isolation and / or purification steps known in the art, such as solvent extraction, recrystallization and / or chromatography. Otherwise, the starting compounds of formula (II) may be reacted in the form of their various salts, esters or silyl derivatives. The silyl derivatives may be prepared by silylating a compound of formula II with a known silylating agent, such as a compound of formula A wherein R and R are lower alkyl or lower alkoxy, R 'is halogen or phenyl, lower alkoxy or lower alkoxy

189 545 represents an alkyl group and Y represents a reactive group capable of cleavage from the silylating agent.

In the silylating compounds represented by the general formula (A), the lower alkyl group is, for example, methyl, chloromethyl, ethyl, η-propyl, isopropyl, n-butyl or tert-butyl, the halogen is chlorine or bromine, the silylating agent is cleaved and the reactive reactive group, in addition to the aforementioned halogen atom, is N- (trimethylsilyl) trifluoroacetimidoyloxy; N- (trimethylsilyl) acetimidoiloxicsoport; acylamino such as formylamino, acetylamino, propionylamino, butyrylamino or trifluoroacetylamino; trialkylsilylamino such as trimethylsilylamino or chloromethyldimethylsilyl; amino; alkylamino such as methylamino, ethylamino or propylamino; Ν, Ν-dialkylamino such as Ν, Ν-dimethylamino, N- (chloromethyl) -N-methylamino, Ν, Ν-diethylamino, Ν, Ν-dipropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino or N-ethyl-N-propylamino, or a heterocyclic group such as imidazoyl.

Specifically, the silylating agents of formula (A) include: vegyületek-Ο-bis (trimethylsilyl) trifluoroacetamide, N, O-bis (trimethylsilyl) acetamide, bis (dimethylisopropylsilyl) acetamide, trimethyl -silylacetamide, bis (dimethyl tert-butylsilyl) acetamide, N-methyl-N- (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) dimethylamine, hexamethyldisilazane, , 3-bis (chloromethyl) -1,1,3,3-tetramethyldisilazane, N- (trimethylsilyl) imidazole, trimethylchlorosilane, triethylchlorosilane, dimethyldichlorosilane, diethoxy dichloro- silane, tert-butyldimethylchlorosilane, isopropyldimethylchlorosilane, dimethylphenylchlorosilane or chloromethyldimethylchlorosilane.

When tert-butyldimethylchlorosilane or isopropyldimethylchlorosilane is used, the corresponding silyl derivatives can be stably isolated. The silylation reaction utilizes at least 1 molar equivalent, preferably 1 to 3 molar equivalents, of silylating agent (A) per mole of compound (II). The reaction temperature is from 0 ° C to 50 ° C, preferably up to 38 ° C, usually room temperature; and the reaction time may vary from a few minutes to 24 hours. The reaction can be conveniently carried out, for example, in ethyl acetate, dioxane, tetrahydrofuran, N, N-dimethylacetamide, N, N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, acetone, methyl ethyl ketone or acetonitrile or optionally in a mixture thereof. , or in any other solvent which is inert to the reactants. The reaction may also be carried out in the presence of a base. Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate or potassium carbonate may be used; and organic bases such as trialkylamines such as triethylamine, tributylamine, tribenzylamine, N-methylmorpholine or N-methylpiperidine; tertiary amines such as Ν, Ν-dialkylamylines, N, N-dialkylbenzamines, pyridine, picoline or rutidine, or other organic bases such as 1,5-diazabicyclo [2.2.2] octane or 1 , 8-Diazabicyclo [5.4.4.] Undec-7-ene, If this base is liquid, it can also serve as a solvent. A silylated derivative of general formula (II) thus obtained, which has an amino protecting group at R ₂ , can then be converted to the corresponding reactive 1-silyl derivative by deprotection. This latter step is then followed by sulfonation.

Compounds of formula (IV) which form a narrower group of compounds of formula (I) may also be prepared by acylation of a compound of formula (III). To effect acylation, a compound of formula (III) is reacted with an acylating agent. The acylating agent used in this reaction may be an organic carboxylic acid or a reactive derivative thereof which contains an acyl group R ₃ .

Suitable reactive derivatives of organic acids include, but are not limited to, acid anhydrides, reactive amides, and reactive esters. Examples of reactive derivatives of organic acids include:

1. Anhydrides

Acid anhydrides include, for example, halogen hydrogens (such as hydrochloric acid or hydrobromic acid), monoalkyl carbonates, aliphatic carboxylic acids (such as acetic acid, pivalic acid, valeric acid, isopentanoic acid or trichloroacetic acid) such as aromatic carboxylic acids (e.g. mixed anhydrides with benzoic acid) and symmetric acid anhydrides.

2. Reactive amides

Reactive amides include, for example, amides with pyrazole, imidazole, 4-substituted imidazoles, dimethylpyrazole or benzotriazole.

3. Reactive esters

Reactive esters include, but are not limited to, esters such as methyl, ethyl, methoxymethyl, propargyl, 4-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl and mesylphenyl esters and esters with alcohols such as 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide or N-hydroxyphthalamide.

Depending on the nature of the acid used in the particular case, one of the reactive derivatives listed above is selected for the particular case. If, on the other hand, the free acid is used as the acylating agent; then acylation is preferably carried out in the presence of a condensing agent. Examples of suitable condensing agents include Ν, Ν'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N '- (4-diethylaminocyclohexyl) -carbodiimide or N-. ethyl-N '- (3-dimethylaminopropyl) carbodiimide.

The acylation is usually carried out in a solvent. Suitable solvents include 61

Water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine and other known organic solvents which are inert to the reactants. Of these, hydrophilic solvents, for example mixtures with water, may be used.

The acylation may be carried out in the presence of an inorganic base (such as sodium hydroxide, sodium carbonate, potassium carbonate or sodium bicarbonate) or an organic base. The latter may be trialkylamines such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine or N-methylpiperidine; organic tertiary amines such as N, N-dialkylaniline, Ν, Ν-dialkylbenzylamine, pyridine, picoline or lutidine; tetra (n-butyl) ammonium hydroxide; l, 5-diazabicyclo [4.3.0] non-5-ene; 1,4-diazabicyclo [2.2.2] octane or 1,8-diazabicyclo [5.4.4] undec-7-ene. When the base or the aforementioned condensing agent is in liquid form, it may also serve as a solvent. The reaction temperature is not a critical parameter, however, the reaction is usually carried out under cooling or at room temperature.

When a starting compound of formula (III), a reactive derivative thereof at an amino group, a salt thereof, or an acylating agent, contains at least one asymmetric carbon atom, the corresponding stereoisomers may be acylated alone or as mixtures thereof. If the acylation product is a mixture of the corresponding isomers, the individual isomers may be separated, if desired, by conventional means such as column chromatography or recrystallization.

Thus, the compounds of formula (111) used as starting materials for the acylation reaction may also be used in the form of their salts or, for example, their silyl derivatives. Examples of these salts are the previously described salts of the final compounds of formula (I), while the silyl derivatives include the previously described silyl derivatives of the compounds of formula (II).

If the starting material used in the acylation reaction is in the form of a salt, the resulting final product of formula (V) may also be in the form of a salt. If the product is obtained in the form of a salt, this salt can be converted to another salt by the same procedure as described above for the conversion of salts of the final products of formula (I).

The compounds of formula (IV) isolated in the form of a salt can also be converted into the free acids if desired. For this purpose, the above-mentioned methods for liberating the free acid from the salts of the final products of formula (I) may also be used.

The deprotected compounds of formula (I) are valuable compounds as intermediates in pharmaceuticals and can be converted to the deprotected compounds of formula (I) by deprotection.

The deprotection of the compounds of formula (I) may be carried out by selective methods well known in the art. Such methods include those using the acid or base, the reduction method, the hydrazine method, or thiourea or

Method using sodium salt of N-methyldithiocarbamic acid.

Depending on the type of the protecting group and other conditions for deprotection, inorganic acids such as hydrochloric, sulfuric or phosphoric acid and organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, and acidic ion exchange resins. In the base-based method, depending on the type of protecting group and other conditions for deprotection, inorganic bases such as hydroxides or carbonates of alkali metals (such as sodium or potassium) or alkaline-earth metals (such as calcium or magnesium), and organic bases, e.g. or quaternary ammonium salts and basic ion exchange resins.

When the method based on the use of an acid or a base is carried out in the presence of a solvent, the solvent is usually a hydrophilic organic solvent, water or a mixture thereof.

Depending on the type of protecting group and other conditions for deprotection, metals (e.g. tin or zinc), metal compounds (e.g. chromium (II) chloride or chromium (III) acetate) with an acid such as an organic or inorganic acid (e.g. with propionic acid or hydrochloric acid) or metal catalysts suitable for catalytic reduction. The catalyst used for such catalytic reduction is, for example, a platinum catalyst (such as platinum wire, platinum sponge, platinum carbon black, platinum oxide or colloidal platinum), a palladium catalyst (e.g. silica gel supported palladium catalyst), reduced nickel, nickel oxide, Raney nickel or Urushihara nickel.

As mentioned, another reduction method is based on the combination of a metal compound and an acid. For this purpose, a mixture of a metal compound (such as an iron or chromium compound) and an organic acid (formic acid, acetic acid or propionic acid) or an inorganic acid (e.g. hydrochloric acid) is used. This reduction method is also usually employed in a solvent. For example, in the catalytic reduction method, the reaction is usually carried out in the presence of an alcohol (such as methanol, ethanol, propanol or isopropanol) or ethyl acetate. For the metal and acid reduction method, for example, water or acetone may be used as the solvent, but if the acid is in liquid form, it may also serve as a solvent.

Cleavage of the protecting groups can also be carried out over a wide range of temperatures by cooling or heating.

If the protecting group is a residue derived from an organic carboxylic acid and has a substituent on the carbon atom adjacent to the carbonyl group7

189 545, such as the free amino, hydroxyl, mercapto, carboxyl or sulfo group, it may be advantageous to pre-react with such a substituent group to render the carboxyl group more reactive and then remove the protecting group. For example, if said substituent group is a free amino group, then this free amino group is first converted to a thioureido group prior to the deacylation reaction, so that the protecting group can be removed by standard methods for cleavage of the peptide bond. The reaction temperature is not a critical parameter, however, it may be chosen depending on the type of protecting group, the method of cleavage of the protecting group, although the reaction is preferably carried out under cooling or with slight heating.

When R is a carboxyl group, in some cases the derivative of the carboxyl group is converted to the free carboxyl group during the reaction. These cases are also considered to be within the scope of the invention.

The resulting unprotected product of formula (1) may, if desired, be converted into the corresponding salt by conventional means.

The starting compounds of formulas II and III can be prepared as follows.

For example, compounds of formula II having an acyloxy group at R ₄ may be prepared according to Tetrahedron Letters, 1978, 4059, or U.S. Pat. No. 76,570/1979. in the Japanese Patent Application. When R ₄ is (X) of the formula substituted ditiocsoport then in Chemical Communication, 1971, Vol 845 described method or its analogous method can be applied. While HR ₄ is different from acyloxy or substituted dithio, the method described in Annalene Dérie Chemie, 1974, 539 may be used, alternatively as shown in Schemes A and B.

In Schemes A and B, R ₂ , R ₃ , R ₄ and X are as previously defined and R _{8 is a} protected amino group.

The following Examples, Reference Examples and Experimental Examples illustrate the invention. In these examples, NMR spectra were recorded on Varian HA 100 (100 MHz), EM 390 (90 MHz) and T 60 (60 MHz) instruments, using tetramethylsilane as reference material and delta values in ppm. The following abbreviations are used to indicate chemical shifts: s - singlet; d = doublet; dd = doublet of doublets; t = triplet; q = quartet; m = multiplet; ABq = quartet of type AB; J = switching constant; THF = tetrahydrofuran; DMF = dimethylformamide; DMSO = dimethyl sulfoxide.

Column chromatography on silica gel was carried out using Merck Co. (Federal Republic of Germany) brand Kiesel Gel 60 (230-400 mesh) and elution was carried out by thin layer chromatography. Thin layer chromatography was performed using Merck Co. plate "Kiesel Gel 60 F 2 _S4 " as _eluant , eluting with solvent or solvent mixture and developing under ultraviolet light.

The fractions were collected in which Rf of the desired compound was identical to the TLC plate, the main spot on the loaded mixture, Tlc _Rf -értékével.

Chromatography on a XAD-II resin column was eluted with a mixture of water and 20% v / v ethanol. Fractions that were absorbed at 254 nanometers in the ultraviolet spectrum of the LKB UVICORD 2 were collected. The combined fractions were then lyophilized.

Experimental example

In this example, the inhibitory concentration that results in a 50% reduction in enzyme activity is determined.

As a typical example of cephalosporinases, β-lactamase produced by Enterobacter cloacae strain PN 1282 is used. The β-lactamase is incubated for 10 minutes at 30 ° C in 0.05 M phosphate buffer pH 7 with appropriate dilution. Cephalotin was then added to a final concentration of 0.1 mmol, and the enzymatic reaction was allowed to proceed for 10 minutes. Enzyme activity is then determined by the micro-iodometric method described in Journal of General Microbiology, 33, 121 (1963). The inhibitor concentration required to reduce the enzyme activity by 50% is reported as I ₅₀ . The I ₅₀ values for Enterobacter cloacae are given in Table 1.

/. spreadsheet

Test compound (pg / ml) (3R, 4R) -4-Methylthio-3- [2- (2-amino-thiazol-4-yl) -2- (1-carboxy-1-methyl-ethoxyimino) -acetamide ] -2-Oxo-azetidine-1-sulfonic acid sodium salt of (3R, 4S) -3- [2- (2-aminothiazol-4-yl) -2-methoxyimino) -acetamido] -4-phenylthio-2- 0.027 Oxoazetidine-1-sulfonic acid sodium salt of (3R, 4R) -3- [2- (2-aminothiazol-4-yl) -2 (methoxyimino) acetamido] -4-methylthio-2-O 3-Oxoazetidine-1-sulfonic acid sodium salt of (3R, 4R) -3- [3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarboxamido] -4-methylthio-2-oxo-0.045 azetidine-l-sulfonic acid sodium salt

Example 1:

A solution of 21.9 g of (3S, 4S) -4-acetoxy-3- [benzyloxycarboxamido] -2-oxoazetidine-1- [alpha-isopropylidene] acetic acid in 400 mL of methylene chloride

It is treated with 189,545 ozone until the reaction mixture turns blue. Methyl sulfide (10 mL) was added followed by a small amount of sodium methylate (350 mL) in methanol. 10.6 g of (3S, 4S) -4-acetoxy-3- [benzyloxycarboxamido] -2-oxoazetidine are isolated in the reaction mixture.

I R spectrum nNew, ^cm-1: 3480, 3430, 1815 (shoulder), 1800, 1770, 1725, 1695, 1522, 1260 and 1240th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.13 (s, CH ₃ ),

4.80 (dd, J = 2.8Hz, C ₃ -H), 5.20 (s, -CH ₂ -),

5.90 (d, J = 2Hz, C ₄ H), 6.10 (d, J = 8Hz, NH),

7.26 (broad s, NH) and 7.43 (s, aromatic H).

Reference Example 2 Methyl g (3S, 4S) -4-acetoxy-3- (phenoxyacetamido) -2-oxoazetidine-1- (alpha-isopropylidene) acetic acid as described in Reference Example 1, treated with 2.1 g (3S). 4S) -4-acetoxy-3- (phenoxyacetamido) -2-oxoazetidine is obtained.

IR spectrum cm- ¹ : 3325.1805, 1760.1745, 1670, 1530, 1230 and 1218.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.17 (s, CH ₃ ), 4.62 (s, -CH ₂ -), 5.03 (dd, J = 2.7Hz, C ₃ -H), 6.03 (d, J = 2Hz, C ₄ H) and 6.95-7.80 (m, NH, aromatic H).

Reference Example 3

In aqueous acetone, 1 g of (3R, 4R) -4-methylthio-3- (phenoxyacetamido) -2-oxoazetidine-1- (alpha-isopropylidene) acetic acid methyl ester was treated with 1.2 g of potassium permanganate and 2 ml of acetic acid. 0.486 g of (3R, 4R) -4-methylsulfonyl-3- (phenoxyacetamido) -2-oxoazetidine are obtained.

IR spectra: cm- ¹ : 3290, 1770, 1675, 1525, 1290, 1275 and 1215.

Nuclear Magnetic Resonance Spectrum (d ₆ DMSO, ppm): 3.16 (s, CH ₃ ),

4.53 (s, -CH ₂ -), 5.16 (d, J = 25Hz, C ₄ -H), 5.71 (dd, J = 5.1Hz, C ₃ -H), 6.80- 7.43 (m, aromatic H),

8.35 (d, J = 10 Hz, NH) and 9.51 (s, NH).

Reference Example 4

4.5 g of (3R, 4R) -3- (benzyloxycarboxamido) -4-methylthio-2-oxoazetidine-1- (alpha-isopropylidene) acetic acid methyl ester were treated in the same manner as in Reference Example 3, 2.3 g (3R). 4R) -3- (Benzyloxycarboxamido) -4- (methylsulfonyl) -2-oxoazetidine is obtained.

IR .nu ™ ^{r cm-1:} 3320.3275, 1765, 1688, 1512, 1292, 1275, 1252 and 1230th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.96 (s, CH ₃ ), 5.07 (d, J = 5Hz, C ₄ -H), 5.17 (s, -CH ₂ -), 5.50 (dd, J = 5.10Hz, C ₃ -H), 7.42 (s, aromatic H), 7.76 (d, J = 10Hz, NH) and 9.40 (s, NH).

Reference Example 5 Methyl ester of (3R, 4R) -4-methylthio-3- (phenoxyacetamido) -2-oxoazetidine-1- (alpha-isopropylidene) acetic acid as in Reference Example 1, treated with 1.34 g (3R). 4R) -4- (methylsulfinyl) -3- (phenoxyacetamido) -2-oxoazetidine is obtained.

IR .nu ® * _x ^r cm ^-1: 3275, 1765, 1665, 1530 and 1212th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.58 (s, CH ₃ ), 4.70 (s, -CH ₂ -), 4.92 (d, J = 5Hz, C ₄ H), 5.75 (dd, J = 5.10Hz, C ₃ -H), 6.93-7.65 (m, aromatic H), 8.61 (d, J = 10Hz, NH) and 9.28 (s). , NH).

Reference Example 6

3.29 g of (3R, 4R) -4-ethylthio-3- (phenoxyacetamido) -2-oxoazetidine-1- (alpha-isopropylidene) -acetic acid methyl ester were treated with the same procedure as in Reference Example 1 and 1.36 g (3R) 4R) -4- (ethylsulfinyl) -3- (phenoxyacetamido) -2-oxoazetidine is obtained.

IR nu ^ cnf ^1: 3310, 3160, 1760, 1685 and 1208th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.23 (t, J = 8Hz, CH ₃ ), 2.70 (q, J = 8Hz, -CH ₂ -), 4.65 (s, -CH _2- ), 4.75 (d, J = 5Hz, C ₄ -H), 5.78 (dd, J = 5.10Hz, CH ₃ -H), 6.85-7.63 (m, aromatic H). )

9.10 (d, J = 10Hz, NH) and 9.18 (s, NH).

Reference Example 7

Under ice-cooling, a solution of (3S, 4S) -4-acetoxy-3- (phenoxyacetamido) -2-oxoazetidine (1.38 g) in 80 mL of 80% ethanol was added dropwise from a solution of 0.441 g of sodium ethyl sulfide in ethanol. ml. The resulting mixture was stirred under ice-cooling for 30 minutes and then at room temperature for 15 minutes. The ethanol is then distilled off under reduced pressure and the aqueous phase is extracted twice with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1).

On the one hand, 0.680 g of (3R, 4S) -4-ethylthio-3- (phenoxyacetamido) -2-oxoazetidine are obtained.

IR Spectrum? Cm ^-1 : 3270, 3150, 1752, 1659.

NMR (CDC1 ₃ ppm): 1.27 (t, J = 7Hz, _CH3), 2.62 (q, J = 7 Hz, - CH ₂ -), 4.46 (s, _-CH2 - ), 4.80 (d, J = 2Hz, C ₄ -H), 4.83 (dd, J = 2.9Hz, CH ₃ -H), 6.70-7.40 (m, aromatic H, NH ) and 7.68 (d, J = 9Hz, NH).

On the other hand, 0.164 g of (3R, 4R) -4-ethylthio-3- (phenoxyacetamido) -2-oxoazetidine is obtained.

IR spectrum New cm- ¹ : 3260, 1770, 1725, 1665 and 1525.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.23 (t, J = 7Hz, CH ₃ ), 2.52 (q, J = 7Hz, -CH ₂ -), 4.66 (s,

-9I

189,545 - CH ₂ -), 5.05 (d, J = 5Hz, C ₄ --H), 5.75 (dd, J = 5.10Hz, CH ₃ --H), 6.60 (bs, NH ) and

6.90-7.70 (m, aromatic Η, NH).

Reference Example 8

To a solution of (3R, 4S) -4-ethylthio-3- (phenoxyacetamido) -2-oxoazetidine (0.224 g) in methanol (3 mL) was added 30% aqueous hydrogen peroxide (0.16 mL) and the resulting mixture was stirred at room temperature for 4 hours. stir for 1 hour. A further 0.1 mL of 30% aqueous hydrogen peroxide solution was added and stirring continued for a further 4 hours. Water (10 mL) was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give (3R, 4S) -4- (ethylsulfinyl) -3- (phenoxyacetamido) -2-oxoazetidine (0.2 g).

IR spectrum cm- ¹ : 3350, 3270, 1765, 1750 and 1690.

NMR (d _e -DMSO, ppm): 1.22 (3H, t, J = 8 Hz, _CH3), 2.75 (q, J = 8Hz, _-CH2 -), 4.65 (s, -CH ₂ -), 4.78 (d, J = 2Hz, CH ₄ -H), 5.15 (dd, J = 2.10Hz, CH ₃ -H), 6.93-7.60 (m, aromatic H),

8.95 (s, NH) and 9.08 (d, J = 10Hz, NH).

Reference Example 9

To a solution of (3S, 4S) -4-acetoxy-3- (phenoxyacetamido) 2-oxoazetidine (0.494 g) in 50 ml of methanol (14 ml) was added 0.51 g of sodium methyl sulfinate and the resulting mixture was stirred at room temperature. Stir for 18 hours. Methanol was distilled off under reduced pressure to give (3R, 4S) -4- (methylsulfonyl) -3- (phenoxyacetamido) -2-oxoazetidine (222 mg).

IR nu ^ _x ^{r cm-1:} 3290, 1798, 1670.1525, 1305 and 1130th

NMR (d _e -DMSO, ppm): 3.08 (s, _CH3), 4.60 (s, _-CH2 -), 5.02 (d, J = 2Hz, C ₄ -H);

5.23 (dd, J = 2.9Hz, C ₃ -H), 6.95-7.63 (m, aromatic H), 9.05 (d, J = 9Hz, NH), and 9.28 (s). , 4H).

Reference Example 10

In the same manner as in Reference Example 9, 1.4 g of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine were treated with 0.5 g of sodium methyl sulfinate. 178 DEG-180 DEG C. (colorless crystals), m.p. 178-180 [deg.] C., yielding (3R, 4S) -3-benzyloxycarboxamido-4- (methylsulfonyl) -2-oxoazetidine (0.75 g).

IR nu ^r ^ ® cm ^- ': 3300, 1800, 1695, 1530, 1300, 1265 and 1115th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.06 (s, CH ₃ ), 4.82 (dd, J = 8.2Hz, C ₃ -H), 5.00 (d, J = 2Hz, C ₄ -H), 5.16 (s, -CH ₂ -), 7.43 (s, aromatic H), 8.33 (d, J = 8Hz, NH) and 9.33 (broad s, NH). .

Reference Example 11 (3S, 4S) -4-Acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine (3 g) in methanol was added and 2.36 g of zinc acetate were added thereto and the reaction mixture was refluxed. reflux for 45 minutes. The solvent was distilled off, and ethyl acetate and water were added to the residue. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate / n-hexane (1: 1) as eluent to give (3S, 4S) -3- (benzyloxycarboxamido) -4-methoxy-2-oxoazetidine (1.37 g) and on the other hand, 0.82 g of (3S, 4R) -3- (benzyloxycarboxamido) -4-methoxy-2-oxoazetidine (B), identification data (B):

IR .nu ™ ^{r cm-1:} 3320, 3240, 1668, 1740, 1720 and 1700th

NMR (d _e -DMSO, ppm): 3.23 (s, _CH3), 4.79 (dd, J = 4.10 Hz, C ₃ -H), 4.91 (d, J = 4Hz , C ₄ H, 5.03 (s, -CH ₂ -), 7.33 (s, aromatic H), 7.87 (d, J = 10 Hz, NH) and 8.86 (s, NH). .

(A) Identification Information:

IR spectrum cm- ¹ : 3370, 3320, 1775, 1758, 1690.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.26 (s, CH ₃ ), 4.23 (dd, J = 1.59 Hz, C ₃ -H), 4.79 (d, J = 1). , 5Hz, C ₄ -H), 5.03 (s, -CH ₂ -), 7.33 (s, aromatic H), 7.94 (d, J = 9Hz, NH), and 8.86 (s, NH).

Reference Example 12

All. In the same manner as in Reference Example 1, but starting from 1.5 g of (3R, 4R) -4-methylsulfonyl-3- (phenoxyacetamido) -2-oxoazetidine and 1.11 g of zinc acetate, 3S, 4S) -4-methoxy-3- (phenoxyacetamido-2-oxoazetidine (A) and 0.287 g of (3S, 4R) -4-methoxy-3- (phenoxyacetamido) -2-oxoazetidine (B)). ) we get.

(A) Identification Information:

IR nu * ® ^{r cm-1:} 3280, 3175, 1760 and 1663rd

Nuclear Magnetic Resonance Spectrum (d ₆ -aceton, ppm): 3.35 (s, CH ₃ ),

4.51 (s, -CH ₂ -), 4.68 (dd, J = 1.5 and 9Hz, C ₃ -H), 4.98 (d, J = 1.5Hz, C ₄ -H), 6.83-7.43 (m, aromatic H) and 7.80-8.30 (m, NH).

(B) your identification information:

IR .nu ® * _x ^{r cm-1:} 3320, 3200, 1763, 1658th

Reference Example 13 To a solution of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine (g) in THF (30 mL) was added palladium on carbon (500 mg) and the resulting mixture was stirred under a stream of hydrogen for 1 h. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to a volume of nearly 10 ml.

At the same time, 20 g of methylene chloride are first 2 g

-101. 189,545 syn-2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetic acid was added followed by cooling with ice (0.87 g) and triethylamine (1.5 g). The resulting reaction mixture was stirred under ice-cooling for 5 minutes and then at room temperature for 30 minutes and then concentrated under reduced pressure. The residue was washed with hexane, then tetrahydrofuran (10 mL) was added and the insoluble material was filtered off. Under ice-cooling, the filtrate is added dropwise to a mixture of the concentrate obtained in the preceding paragraph and 3 ml of propylene oxide. The solvent was distilled off under reduced pressure and the resulting ethyl acetate solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate / n-hexane (2: 1) as the eluent to afford (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamidothiazole-4-). il) -2- (methoxyimino) acetamido] -2-oxoazetidine gave 0.170 g of the anti-isomer, 0.20 g of the syn isomer and 0.30 g of the mixture of the two isomers.

Identification of the syn isomer:

IR spectrum cm- ¹ : 3270, 1770, 1740, 1720,

1665 and 1545.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.17 (s, CH 3, 4.00 (s, CH ₃ ), 4.40 (s, -CH ₂ -), 4.90 (dd, J = 2.8Hz, C ₃ -H), 5.93 (d, J = 2Hz, C ₄ -H), 7.52 (s, XXV. of the above formula), 9.30 (s, NH), 9.43 (d, J = 8Hz, NH) and 12.87 (s, NH).

Identification of the anti-isomer:

IR: cm- ¹ : 3250, 1770, 1750 (shoulder), 1665 and 1540.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.13 (s, CH ₃ ), 4.07 (s, CH 3, 4.40 (s, -CH ₂ -), 4.90 (dd, J = 2.9Hz, C 1 -H), 5.88 (d, J = 2Hz, C ₄ -H), 8.02 (s, part of Formula XXV), 9.30 (d, J = 9Hz, NH), 9.35 (s, NH) and 12.77 (s, NH).

14. Reference Example

In the same manner as in Reference Example 13, but starting from 0.298 g of (3R, 4R) -3-benzyloxycarboxamido) -4- (methylsulfonyl) -2-oxoazetidine and 0.638 g of D-2- (4-ethyl-2 , 3-Dioxo-piperazine-carboxamido) -2-phenyl-acetic acid, using 0.114 g of (3R, 4R) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2 -phenylacetamido] -4- (methylsulfonyl) -2-oxoazetidine was obtained.

IR nu f * _x ^{r cm-1:} 3270, 1778, 1700, 1668 and 1500th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.09 (t, J = 7Hz, CH 3), 2.27 (s, CH 3, 3.40 (q, J = 7Hz, -CH ₂ -), 3, 44-3.66 (m, -CH ₂ -), 3.78-A, O ₂ (m, -CH ₂ -), 4.94 (d, J = 5Hz, C ₄ -H), 5.61 ( dd, J = 5.9Hz, C 1 -H), 5.72 (d, J = 7Hz, Part XXVI), 7.25-7.54 (m, aromatic H), 9.08 (d, J 9Hz, NH), 9.33 (s, NH) and 9.85 (d, J = 7Hz, NH).

Reference Example 75

In the same manner as in Reference Example 13, but starting from 0.298 g of (3R, 4R) -3-benzyloxycarboxamido) -4- (methylsulfonyl) -2-oxoazetidine and 0.555 g of syn-2- (2-chloroacetamidothiazole). -4-yl) -2- (methoxyimido) -acetic acid (0.205 g) in (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) ) -acetamido] -4- (methylsulfonyl) -2-oxoazetidine is obtained in the form of a mixture of the color and the anti-isomer.

Identification of the syn isomer:

IR spectrum cm- ¹ : 3370, 3270, 1790, 1680 and 1540.

NMR (d _e -DMSO, ppm): 3.00 (s, CH), 3.93 (s, CH), 4.33 (s, _-CH2 -), 4.93 (d, J = 5Hz, C ₄ - H), 5.57 (dd, J = 5.9 Hz, C ₃ - H),

7.53 (s, part XXVII), 8.67 (d, J = 9Hz, NH), 9.40 (s, NH) and 12.77 (s, NH).

Identification of the anti-isomer:

IR: cm- ¹ : 3380, 3250, 1790, 1680 and 1540.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.97 (s, CH 3), 3.95 (s, CH 3), 4.27 (s, -CH ₂ -), 5.07 (d, J = 5Hz) , C ₄ H), 5.75 (dd, J = 5.9Hz, C ₃ H),

7.99 (s, part XXVII), 8.67 (d, J = 9Hz, NH), 9.40 (s, NH) and 12.77 (s, NH).

Reference Example 16

To a solution of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine (1.12 g) in tetrahydrofuran (30 mL) was added palladium on carbon (400 mg) and the resulting mixture was stirred under a stream of hydrogen for 1 hour. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to a volume of 5 ml.

At the same time, 0.475 g of diphosgene are added to a solution of 0.410 g of dimethylformamide in 10 ml of methylene chloride at -10 [deg.] C., and the resulting mixture is stirred at room temperature for 15 minutes. Subsequently, 1.23 g of syn-2- (2-chloroacetamidothiazol-4-yl) -2- (isopropoxyimino) acetic acid and 0.530 g of triethylamine are added at -60 ° C to -50 ° C. 15 ml of methylene chloride. The resulting mixture was stirred at -40 ° C to -30 ° C for 1.5 hours and then cooled to -60 ° C and

To 50 ° C, at this temperature, first 0.490 g of triethylamine and then the tetrahydrofuran solution prepared as described in the preceding paragraph are added. The reaction mixture was allowed to stand at room temperature for one hour, and then the solvent was evaporated under reduced pressure. The remaining ethyl acetate solution was washed with water and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column using a 2: 1 by volume mixture of ethyl acetate and n-hexane as the eluent,

1.23 g of syn (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (isopropoxyimino) acetamido] -2-oxoazetidine are obtained. .

-11.189,545

IR spectra: cm-1: 3280, 1762, 1670 and 1226.

NMR (d _e -DMSO, ppm): 1.25 (d, _CH3), 2.13 (s, _CH3), 4.37 (s, - CH ₂ -), from 4.30 to 4, 67 (m, part formula XXVI.), 4.87 (d, J = 8Hz, _C3 -H), 5.89 (d, J = 1 Hz, C ₄ -H), 7.43 (s, XXVII), 9.29 (s, NH), 9.32 (d, J = 8Hz, NH) and 13.05 (s, NH).

Reference Example 17

To a solution of (3S, 4S) -3- (benzyloxycarboxamido) -4-methoxy-2-oxoazetidine (0.300 g) in tetrahydrofuran (10 mL) was added palladium on carbon (150 mg) and the resulting mixture was stirred under a stream of hydrogen gas for 1 hour. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to a volume of 3 ml.

However, to a solution of 0.383 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetic acid in 5 ml of dimethylformamide was added 0.215 g of N-hydroxy-5-norbornene-2,3-dicarboximide. and then 0.248 g of dicyclohexylcarbodiimide was added and the resulting reaction mixture was allowed to stand at room temperature for 3 hours with stirring. Subsequently, the concentrated solution obtained as described in the previous paragraph is added to the mixture and the mixture is stirred for a further 17 hours. The insoluble material is filtered off and the filtrate is concentrated under reduced pressure. Ethyl acetate and tetrahydrofuran were added to the residue. The resulting mixture was washed first with 5% aqueous sodium bicarbonate solution, then with water, dried over magnesium sulfate and concentrated under reduced pressure. 0.250 g of (3S, 4S) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4-methoxy-2-oxoazetidine are obtained.

IR .nu ™ ^r cm⁻¹: 3275, 1770, 1710, 1670 and 1508th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.08 (t, J = 7Hz, CH ₃ ), 3.23 (s, CH ₃ ), 3.80 (q, J = 7Hz, -CH ₂ -). ), 3.43 to 3.66 (m, - CH ₂ -), 3.80-4.07 (m, _-CH2 -), 4.41 (dd, J = 8Hz, _C3 -H ), 4.67 (d, J = 1 Hz, C ₄ -H), 5.42 (d, J = 7 Hz, sub-formula XXVI.), 7.35 (s, aromatic H), 8.98 (s, NH), 9.09 (d, J = 8Hz, NH) and 9.78 (d, J = 7Hz, NH).

Reference Example 18

In the same manner as in Reference Example 17, but starting from 0.300 g of (3S, 4R) -3-benzyloxycarboxamido-4-methoxy-2-oxoazetidine and 0.383 g of D-2- (4-ethyl-2,3 -dioxo-1-piperazinocarboxamido) -2-phenylacetic acid (0.2Sg, (3S, 4R) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamide) ] -4-methoxy-2-oxoazetidine is obtained.

IR .nu ™ ^{r cm-1:} 3275, 1770, 1700, 1665, 1500th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.07 (t, J = 7Hz, CH ₃ ), 2.85 (s, CH ₃ ), 3.38 (q, J = 7Hz, --CH ₂ -). ), 3.40-3.67 (m, -CH ₂ -), 3.73-4.03 (m, '

-CH ₂ -), 4.80 (d, J = 4Hz, C ₄ -H), 5.07 (dd, J = 4-9Hz, C ₃ -H), 5.58 (d, J = 7Hz) , Part XXVI), 7.33 (s, aromatic H), 8.95 (s, 4H), 9.07 (d, J = 9Hz, NH) and 9.84 (d, J = 7Hz, NH). ).

Reference Example 79

In the same manner as in Reference Example 17, but starting from 2.8 g of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine and 3.2 g of D-2- (4-ethyl- Using 2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetic acid, 1.0 g of (3S, 4S) -4-acetoxy-3- [D-2- (4-ethyl-2,3- dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -2-oxoazetidine is obtained.

IR nu "® ^r cm ^- ': 1785, 1715, 1675 and 1510th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 6Hz, CH ₃ ), 2.05 (s, CH ₃ ), 3.52 (m, -CH ₂ -),

3.90 (m, _-CH2 -), 4.60 (dd, J = 2.8Hz, C ₃ -H),

5.48 (d, J = 6Hz, partial Formula XXVI.), 5.72 (d, J = 7Hz, C ₄ -H), 7.40 (s, aromatic H), 9.06 (d, J = 8Hz, NH), 9.16 (broad s, NH), and 9.78 (d, J = 6Hz, NH).

Reference Example 20

500 mg of sin- (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -2-oxo-azetidine in 10 ml of dimethyl 0.245 g of sodium monomethyl dithiocarbamate are added to the solution of formamide and the resulting mixture is stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and the residue was washed three times with ethyl acetate. The residue was taken up in ethanol and the resulting solution was filtered to remove insoluble material and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: chloroform: methanol = 2: 2: 1 as the eluent. 0.270 g of syn (3S, 4S) -4-acetoxy-3- [2- (2-aminothiazol-4-yl) -2-methoxyimino) acetamido] -2-oxoazetidine are obtained.

IR .nu ™ ^{r cm-1:} 3280, 1770, 1740, 1720, 1660, 1520, 1215 and 1035th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.12 (s, CH ₃ ), 3.70 (s, CH ₃ ), 4.78 (dd, J = 1.8 Hz, CH ₃ -H),

5.88 (d, J = 1 Hz, C ₄ -H), 6.85 (s, Part XXVII.), 7.20 (s, _NH2), 9.30 (s, NH) and 9.33 (d, J = 8Hz, NH).

Reference Example 27

0.380 g of (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine in 1 mL of dimethylformamide A solution of 0.079 g of sodium azide in 1 ml of water was added to the reaction solution, and the resulting mixture was stirred at room temperature for 15 hours. This is followed by 121

Ethyl acetate and saturated brine were added to the reaction mixture (189,545), and the organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (ethyl acetate: chloroform: methanol = 4: 4: 1) to give 0.201 g of syn (3S) -4-azido-3- [2- (2-chloroacetamidothiazole-4-). yl) -2- (methoxyimino) acetamido] -2-oxoazetidine in the form of a cis-trans mixture. IR nu ^ ^{r cm-1:} 3275, 2100, 1765, 1665 and 1540th

Reference Example 22

In the same manner as in Reference Example 21, but 2.2 g of (3S, 4S) -4-acetoxy-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenyl- using acetamido] -2-oxo-azetidine and 0.36 g of sodium azide, 1.6 g of (3S, 4S) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazine) (carboxamido) -2-phenylacetamido] -2-oxoazetidine was obtained.

IR nu ^ ® ^{r cm-1:} 2100, 1780, 1705, 1670 and 1505th

Reference Example 23

In a manner similar to that described in Reference Example 7, 0.415 g of (3R, 4S) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4-methylthio 2-Oxoazetidine was prepared.

IR nu ^ ® ^r cm⁻¹: 1765, 1705, 1670 and 1510th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.09 (t, J = 6Hz, CH 3), 2.06 (s, SCHJ, 3.32 (q, J = 6Hz, -CH 3 -), 3.64 (m, -CH ₂ -), 3.90 (m, -CH ₂ -), 4.68 (dd, J = 2.8Hz, C ₃ -H), 5.46 (d, J = 6Hz, XXVI). ), 5.72 (d, J = 2Hz, C ₄ H), 7.38 (broad s, aromatic H), 8.72 (broad s, NH), 9.18 (d, J = 8Hz). , NH) and 9.78 (d, J = 6Hz, NH).

Reference Example 24

0.90 g of (3R, 4R) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4-methylthio-1- (alpha-isopropylidene) Acetic acid methyl ester is treated successively with ozone in methylene chloride, then with a reducing agent and finally with a base in methanol. 0.42 g of (3R, 4R) -3- [D2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4- (methylsulfinyl) -2- oxoazetidine is obtained.

IR spectra: cm-1: 1775, 1710, 1675 and 1510.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 6Hz, CH ₃ ), 2.08 (s, part XXVIII), 3.41 (q, J = 6Hz, -CH ₂ -), 3.56 (m, --CH ₂ -), 3.90 (m, --CH ₂ -), 4.64 (d, J = 4Hz, C ₄ --H), 5.46 (dd, J = 4.8Hz, C ₃ -H), 5.64 (d, J = 6Hz, partial formula XXVI.), 7.4 (broad s, aromatic H), 9.06 (d, J = 8Hz, NH) , 9.18 (bs, NH) and 9.93 (d, J = 6Hz, NH).

Reference Example 25

Under ice-cooling, a solution of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine (2.78 g) in dimethylformamide (15 mL) was added.

1.11 g of triethylamine and 1.66 g of tert-butyldimethylchlorosilane. The resulting mixture was stirred at room temperature for 5 hours and then poured into ice-cold water / ethyl acetate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2) as eluent to give 2.98 g of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -1- (t butyldimethylsilyl) -2-oxoazetidine.

IR nu _m '' ^cm-1: 3300, 2950, 2930.1750, 1720, 1620, 1250, 1152 and 1045th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 0.23 (s, CH ₃ ), 0.97 (s, t-Bu), 2.05 (s, CH 3, 4.40 (dd, J = 1.8 Hz) , C ₃ -H), 5.05 (s, -CH, -), 5.90 (d, J = 8Hz, NH), 6.04 (d, J = 1Hz, C ₄ -H), and 7 , 23 (s, aromatic H).

Reference Example 26 To a solution of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -1- (tert-butyldimethylsilyl) -2-oxoazetidine in 0.72 g of tetrahydrofuran, 0.3 g of palladium on carbon is added. and the resulting mixture was stirred under a stream of hydrogen gas for 1 hour. After addition of 0.2 g of palladium on carbon, the mixture was stirred for an additional 30 minutes, after which the catalyst was filtered off and the filtrate was concentrated under reduced pressure. 0.387 g of (3S, 4S) -4-acetoxy-3-amino-1- (tert-butyldimethylsilyl) -2-oxoazetidine are obtained.

IR spectrum cm-1: 3375, 3325, 2950, 2930, 1750 and 1230.

NMR (CDC1 _3, ppm): 0.24 (s, CHJ, 0.26 (s, CHJ, 0.97 (s, t-Bu), 1.82 (br s, NH,

2.13 (s, CH 3, 4.16 (d, J = 1Hz, C ₃ -H)) and 5.69 (d, J = 1Hz, C ₄ -H).

Reference Example 27

To a solution of (3S, 4S) -4-acetoxy-3-amino-1- (tert-butyldimethylsilyl) -2-oxoazetidine (0.387 g) in tetrahydrofuran (0.37 g) was added dropwise, under ice-cooling, triethylamine (0.24 g) and then dropwise A solution of phenylacetyl chloride (0.32 g) in tetrahydrofuran was added. After stirring for 1 hour under ice-cooling, the insoluble material is filtered off and the filtrate is concentrated under reduced pressure. The residue was purified on a silica gel column using ethyl acetate / n-hexane (1: 2 by volume) as eluent to give (3S, 4S) -4-acetoxyl- (tert-butyldimethylsilyl) -3- (phenylacetamido) (0.511 g). 2oxoazetidine.

IR spectrum ν cm -1: 3290, 2950, 2930, 1750, 1658, 1525, 1252, 1235 and 1042.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 0.24 (s, CH

-131

189,545

0.97 (s, t-Bu), 2.04 (s, CH ₃ ), 3.55 (s, -CH ₂ -), 4.36 (dd, J = 1.8Hz, C ₃ -H) , 6.06 (d, J = 1Hz, C ₄ H), 6.57 (broad s, NH) and 7.19 (s, aromatic H).

Reference Example 28

In the same manner as in Reference Example 16, but 0.385 g of (3S, 4S) -4-acetoxy-3-amino-1- (tert-butyldimethylsilyl) -2-oxoazetidine and 0.384 g of 2-bromo-2-phenyl Using acetic acid, 0.40 g of (3S, 4S) 4-acetoxy-3- (2-bromo-2-phenylacetamido) -1- (tert-butyldimethylsilyl) -2-oxoazetidine is obtained.

IR nu ^ JCM ^1: 3305,2950,2930, 1750, 1675, 1515 and 1,222th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 0.23 and 0.30 (both s, CH ₃ ), 1.00 (s, t-Bu), 2.13 (s, CH ₃ ),

4.70 (m, _C3 -H), 5.51 (br s, portion of Formula XXVI.), 6.23 and 6.27 (both d, J = 2Hz, C ₄ -H), and 7.47 ( s, aromatic H).

Reference Example 29

In the same manner as in Reference Example 17, but 0.84 g of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine and 1.18 g of 2- (2-oxoimidazolidin-1-yl) using carboxamido) -2- (benzothiophen-3-yl) acetic acid, 0.994 g of (3S, 4S) -4-acetoxy-3- [2- (2-oxo-imidazolidin-1-ylcarboxamido) -2 (benzothiophen-3-yl) ) -acetamido] -2-oxoazetidine was obtained.

IR .nu ® ^ ^{r _l} cm: 1785, 1720.1675, 1520, 1270 and 1228th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.07 (s, CH ₃ ), 3.10-3.53 (m, -CH ₂ -), 3.53-3.90 (m, -CH _2- ), 4.63 and 4.65 (both dd, J = 1.8Hz, C ₃ -H), 5.77 and 5.81 (both d, J = 1Hz, C ₄ -H), 5, 87 (d, J = 8Hz, Part XXVI), 7.30-8.15 (m, aromatic H), 7.59 (s, -NH-),

8.90-9.20 (m, NH) and 9.20 (s, NH).

Reference Example 30 Methyl g (3R, 4R) -4- (benzothiazol-2-yl-dithio) -3- (phenoxyacetamido) -2-oxoazetidine-1- (alpha-isopropylidene) acetic acid as described in Reference Example 1. treated with 1.74 g of (3R, 4R) -4- (benzothiazol-2-yl-dithio) -3- (phenoxyacetamido) -2-oxo-azetidine.

IR spectrum cm- ¹ : 3320, 1800, 1770 and 1660.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 4.68 (s, -CH ₂ -), 5.38 (m, C ₃ -H, C ₄ -H), 6.90-8.08 (m , aromatic H), 9.10 (d, J = 5Hz, NH) and 9.17 (s, 4NH).

Reference Example 31

Under ice-cooling, 0.446 g of (3S, 4S) -4-acetoxy-3- [2- (benzothiophen-3-yl) -2- (2-oxo-imidazolidin-1-ylcarboxamido) -acetamido] -2-oxo-azetidine 4 A solution of sodium azide (0.085 g) in water (2 mL) was added to a solution of di14 (2 mL) in methylene chloride and the resulting mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture and the precipitate was filtered off. 0.331 g of (3S) -4-azido-3- [2- (benzothiophen-3-yl) -2- (2-oxoimidazolidin-1-ylcarboxamido) acetamido] -2-oxoazetidine are obtained.

IR spectra: cm- ¹ : 3270, 2110, 1775, 1720, 1670, 1522 and 1268.

Reference Example 32

Under ice-cooling, 0.308 g of (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxy-imino) -acetamido] -2-oxo-azetidine in 3 mL To a solution of dimethylformamide was added a solution of 0.061 g of sodium azide in 2 ml of water. After stirring at room temperature for 18 hours, water was added and the precipitate was filtered off. 0.216 g of (3S) -4-azido-3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -2-oxo-azetidine are obtained.

IR spectrum cm- ¹ : 3270, 2110, 1768, 1662, 1540 and 1275.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.25 (d, J = 6Hz, CH ₃ ), 4.17 (s, trans-CH ₂ -), 4.36 (s, cis -CH ₂ -). ), 4.25-4.50 (m, part of Formula XXVI),

4.75 (dd, J = 2.8 Hz, trans C ₃ -H), 5.11 (d, J = 2 Hz, trans _C-4-H), 7.39 (s, cis-part formula XXV. ), 7.42 (s, trans-XXV), 9.00 (s, cis -NH), 9.05 (s, trans -NH) 9.27 (d, J = 8Hz, trans -NH) ), 9.43 (d, J = 8Hz, trans-NH), 9.43 (d, J = 8Hz, cis -NH), 12.72 (s, trans -NH) and 12.84 (s, cis -NH). -NH).

Reference Example 33

To a solution of (3S, 4R) -3- (benzyloxycarboxamido) -4-phenylacetoxy) -2-oxoazetidine (0.532 g) in tetrahydrofuran (15 mL) was added palladium carbon black (0.35 g) and the resulting mixture was hydrogenated for 1 hour. stirred. The catalyst is filtered off and the filtrate is concentrated to 7 ml.

At the same time, a solution of 0.154 g of dimethylformamide in 8 ml of methylene chloride at -10 ° C is treated with 0.11 ml of diphosgene and the resulting mixture is stirred at room temperature for 20 minutes. Then, at -60 ° C to -70 ° C, 7 ml of methylene chloride solution containing 0.46 g of 2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetic acid are added dropwise. and 0.213 mg of triethylamine. The reaction mixture was stirred at -25 ° C to -20 ° C for 1.5 hours, cooled to -70 ° C and treated with 0.213 g triethylamine, 2 ml propylene oxide and the tetrahydrofuran solution described in the previous paragraph. . The reaction mixture was allowed to return to room temperature with stirring over an hour and then concentrated under reduced pressure. Tetrahydrofuran was added to the residue and the resulting solution was filtered

From the 189,545 insoluble matter was filtered off. The filtrate was concentrated under reduced pressure and ethyl acetate was added to the residue. The resulting crystals were collected by filtration to give 0.236 g of (3S, 4R) -3- (2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) acetamido] -4- (phenylacetoxy) - 2-oxoazetidine is obtained.

IR spectra: cm- ¹ : 3260, 1770, 1735, 1670, 1545, 1245 and 1042.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.68 (s, -CH ₂ -), 3.90 (s, -CH ₂ -), 4.37 (s, -CH ₂ -),

5.45 (dd, J = 4.9Hz, C ₃ -H), 6.04 (d, J = 4 Hz, C ₄ - H), 7.28 (s, aromatic H), 7.36 (s, XXV), 9.17 (s, NH) and 9.41 (d, J = 9Hz, NH).

Reference Example 34

At -70 ° C 0.815 g of (3R, 4R) -4-acetylthio-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -2-oxo A solution of pivaloyloxymethyl-azetidine-1- (alpha-isopropylidene) acetic acid in 60 ml of methylene chloride was purged with ozone for 14 minutes and then nitrogen for 50 minutes. The solution was then washed with 5% aqueous sodium bisulfite solution and then with water, dried over magnesium sulfate and concentrated under reduced pressure. Methanol (100 ml) and water (2 ml) were added to the residue, and the resulting mixture was stirred for 15 hours and then the solvent was distilled off. The residue was purified on a silica gel column using a 1: 1 by volume mixture of ethyl acetate and n-hexane as eluent. 0.468 g of (3R, 4R) -4-acetylthio-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -2-oxoazetidine are obtained.

IR spectrum ν max cm ^-1 : 3275, 1775, 1708, 1670,

1502.1180.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.08 (t, J = 7Hz, CH ₃ ), 2.07 (s, CH 3), 3.40 (q, J = 7Hz, -CH ₂ -) , 3.40-3.66 (n, -CH ₂ -), 3.8 (M, O 3 (m, -CH ₂ -), 5.30-5.50 (m, C ₃ -H, C _4). -H), 5.53 (d, J = 7Hz, Part XXVI), 7.25-7.56 (m, aromatic H), 8.82 (s, NH), 9.29 (m, NH). ) and 9.87 (d, J = 7Hz, NH).

Reference Example 35 To a solution of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine (g) in tetrahydrofuran (200 mL) was added palladium on carbon (2.5 g) and the mixture was stirred under a stream of hydrogen for 1 hour. stirred. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to a volume of 50 ml. To the concentrate was added 50 ml of methylene chloride under ice-cooling, and a solution of 10.52 g of trityl chloride in 100 ml of methylene chloride was added dropwise. The resulting mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. Diethyl ether was added to the residue and the precipitated crystals were filtered off. 13.1 g of (3S, 4S) -4-acetoxy-3- (tritylamino) -2-oxoazetidine are obtained.

IR nu * ^{"r cm-1:} 3320.1775, 1735, 1230 and 1030th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.85 (s, CH ₃ ),

2.90 (br s, NH), 4.27 (d, J = 1Hz, C ₃ -H), 4.87 (d, J = 1Hz, C ₄ -H), 6.58 (s, NH) and 7.27-7.77 (m, aromatic H).

Reference Example 36

To a solution of (3S, 4S) -4-acetoxy-3- (tritylamino) -2-oxoazetidine (0.7 g) in methanol (10 mL) was added a solution of potassium thioacetate (0.25 g) in water (2 mL) and the resulting mixture was stirred at room temperature for 55 min. Stir at -60 ° C for 30 minutes. Methanol was then distilled off under reduced pressure and ethyl acetate was added to the residue. After washing with water, drying and evaporation under reduced pressure, the resulting residue was purified on a silica gel column using ethyl acetate / n-hexane (1: 1 v / v) as the eluent to give 0.195 g of (3R, 4R) -4-acetylthio-3- (tritylamino) - 2-oxoazetidine.

IR spectra: cm- ¹ : 3290, 1775, 1765, 1690 and 1665.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.30 (s, CH ₃ ), 3.05 (broad s, NH), 4.77 (m, C ₃ -H), 5.13 (d,

J = 5Hz, _C4 -H), 6.57 (s, NH) and 7.20 to 7.73 (m, aromatic H).

0.417 g of the corresponding (3R, 4S) isomer can also be isolated.

IR nu * ® ^r cm⁻¹: 3320, 1760 and 1685th

NMR (CDC1 _3, ppm): 2.15 (s, _CH3), 3.05 (s, NH), 4.23 (d, J = 2, C ₃ _ H), 4.66 (d , J = 2Hz, C ₄ -H), 6.77 (s, NH) and 7.27 to 7.77 (m, aromatic H).

Reference Example 37

Under ice-cooling, a solution of (3R, 4S) -4-acetylthio-3-tritylamino-2-oxoazetidine (0.819 g) in acetone (6 mL) was treated with p-toluenesulfonic acid monohydrate (0.453 g) and allowed to stand for 15 hours. The acetone was then distilled off under reduced pressure, and the resulting residue was washed first with diethyl ether and then dissolved in 20 ml of methylene chloride. To the resulting solution was added 0.174 g of pyridine at -10 ° C, followed by stirring for 5 minutes. This gives a suspension.

At the same time, to a solution of 0.703 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetic acid in 20 ml of methylene chloride are added 0.24 g of trimethylchlorosilane and 0.223 g of triethyl- and the resulting mixture was cooled to room temperature for 40 minutes and then cooled to -25 ° C to -20 ° C. To the resulting solution was added 0.161 g of dimethylformamide and 0.13 ml of diphosgene, and the resulting mixture was stirred for 2 hours and then cooled to -70 ° C. To the mixture was then added 0.223 g of triethylamine and 2 ml of propylene oxide, and the suspension obtained as described in the previous paragraph. The reaction mixture was allowed to warm to room temperature over 1.5 hours and then

-151

189,545 were concentrated under pressure. The residue was purified on a silica gel column using ethyl acetate / n-hexane (1: 1) as eluent to give (3R, 4S) -4-acetylthio-3- [D-2- (4-ethyl-2,3-dioxo) (0.567 g). -1-piperazinecarboxamido) 2-phenylacetamido] -2-oxoazetidine.

IR nNew ^ 'cm ^-': 3275, 1775, 1763, 1670, 1500 and 1180th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.09 (t, J = 7Hz, CH ₃ ), 2.34 (s, CH ₃ ), 3.41 (q, J = 7Hz, -CH ₂ -). ), 3.40-3.70 (m, -CH ₂ -), 3.80-4.05 (m, -CH ₂ -), 4.77 (dd, J = 2.9Hz, C ₃ -H ), 5.10 (d, J = 2Hz, C ₄ H), 7.40 (s, aromatic H). 8.93 (s, NH),

9.26 (d, J = 9Hz, NH) and 9.84 (d, J = 8Hz, NH).

Reference Example 38

Under ice-cooling, a solution of (3R, 4R) -4-acetylthio-3-tritylamino-2-oxoazetidine (0.828 g) in acetone (5 mL) was treated with p-toluenesulfonic acid monohydrate (0.45 g) and the resulting mixture was stirred at room temperature for 1 hour. stir for 1 hour. The acetone was then distilled off under reduced pressure and the residue was washed with diethyl ether and dissolved in methylene chloride (20 mL). To solution A, 0.211 g of pyridine is added at -10 [deg.] C. and stirred for 5 minutes to give a suspension.

At the same time, 0.148 g of diphosgene was added to a solution of 0.18 g of dimethylformamide in 5 ml of methylene chloride at -10 ° C, and the resulting mixture was stirred at room temperature for 30 minutes. Subsequently, to the mixture cooled to -70 ° C was added dropwise a solution of 15 ml of methylene chloride solution containing 0.627 g of 2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetic acid and 0. Contains 25 g of triethylamine. The reaction mixture was stirred at -25 ° C to -20 ° C for 1.5 hours and then cooled to -70 ° C. Subsequently, the suspension prepared as described in the previous paragraph is added to the reaction mixture, followed by 0.25 g of triethylamine and 2 ml of propylene oxide. The temperature of the reaction mixture was then raised to room temperature with stirring within 1 hour, and the reaction mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using ethyl acetate / n-hexane (1: 1 v / v) as the eluent (0.296 g of (3R, 4R) -4-acetylthio-3- [2- (2-chloroacetamidothiazol-4-yl)). -2- (methoxyimino) acetamido] -2-oxoazetidine.

IR spectrum cm- ¹ : 3240, 1770, 1755, 1655 and 1530.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.87 (s, CH ₃ ), 3.95 (s, OCH ₃ ), 4.38 (s, -CH ₂ -), 5.36 (dd, J = 5.8Hz, C ₃ -H), 5.68 (d, J = 5Hz, C ₄ -H), 7.56 (s, part XXVII), 8.72 (d, J = 8Hz). NH);

8.99 (s, NH) and 12.87 (s, NH).

Reference Example 39

In the same manner as in Reference Example 38, on the one hand, 0.805 g of (3R, 4S) -4-acetylthio-3-tritylamino) -2-oxoazetidine, 0.437 g of p-toluenesulfonic acid monohydrate and 0.19 g of pyridine, on the other hand, 0.175 g of dimethylformamide, 0.144 ml of diphosgene, 0.61 g of 2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetic acid, 0.243 g of triethylamine and 2 ml of propylene oxide 0.548 g of (3R, 4S) -4-acetylthio-3- (2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine are obtained.

IR spectra? / Cm ^-1 : 3260, 1752, 1690, 1662 and 1525.

Nuclear Magnetic Resonance Spectrum (d ₆ DMSO, ppm): 2.40 (s, CH ₃ ), 3.90 (s, CH ₃ ), 4.34 (s, -CH ₂ -), 4.93 (dd, J = 2.8Hz, C ₃ - H), 5.21 (d, J = 2Hz, C ₄ -H), 7.42 (s, part XXV), 8.97 (s, NH), 9. 40 (d, J = 8Hz, NH) and 12.93 (s, NH).

Reference Example 40

To a solution of 0.48 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetic acid in 10 ml of methylene chloride is added 0.18 g of trimethylchlorosilane and 0.17 g of g of triethylamine. The reaction mixture was stirred at room temperature for 30 minutes, cooled to -25 ° C and -20 ° C, and 0.12 g of dimethylformamide and 0.10 ml of diphosgene were added. The resulting mixture was then stirred for 2 hours and then cooled to -70 ° C. Thereafter, a solution of (3R, 4R) -3-amino-4- (methylsulfonyl) -2-oxoazetidine (0.17 g) in a mixture of 3 ml of dimethylamine and 2 ml of propylene oxide was added first. added. The temperature of the reaction mixture was then raised to room temperature within 1.5 hours and the reaction mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using ethyl acetate: n-hexane (1: 1) as eluent. 0.418 g of (3R, 4R) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4- (methylsulfonyl) -2-oxo- azetidine is obtained which has the same IR and NMR spectra. with the appropriate spectra of the product prepared in Reference Example.

Reference Example 41

At 10 ° C, to a solution of 0.122 g of dimethylformamide in 5 ml of methylene chloride was added 0.10 ml of diphosgene, and the resulting mixture was stirred at room temperature for 30 minutes and then cooled to -70 ° C. Thereafter, 10 ml of a methylene chloride solution containing 0.427 g of 2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetic acid and 0.17 g of triethylamine are added dropwise. The resulting mixture was then stirred at -25 ° C to -20 ° C for 2 hours, then cooled to -70 ° C and 0.229 g of (3R, 4R) -3-amino-4-methylsulfonyl was added. 2-oxoazetidine in a mixture of 3 ml of dimethylamine and 2 ml of propylene oxide. Prior to the addition of this solution, 0.17 g of triethylamine was added to the reaction mixture. The reaction mixture was brought to room temperature within 1.5 hours and then concentrated under reduced pressure. Mara-161

The residue was purified on a silica gel column using ethyl acetate / n-hexane (1: 1 v / v) as eluent to give (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (0.415g). methoxyimino) acetamido] -4- (methylsulfonyl) -2-oxoazetidine. The product was found to be identical to the syn isomer prepared according to Reference Example 15 on the basis of spectral data.

Reference Example 42 To a solution of (3S, 4S) -4-acetoxy-3- (trityl-amino) -2-oxoazetidine (g) in methanol (30 mL) was added 1.7 g of zinc acetate and the resulting mixture was refluxed for 30 minutes. . The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using ethyl acetate / n-hexane (1: 1 v / v) to give (3S, 4R) -4-methoxy-3- (tritylamino) -2-oxoazetidine (0.912 g).

IR .nu ™ ^{r cm-1:} 3270, 3210, 1772, 1725 and 1097th

NMR (CDC1 _3, ppm): 2.98 (s, _OCH3), 3.01 (d, J = 9Hz, NH), 3.88 (d, J = 4 Hz, C ₄ -H), 4 , 08 (dd, J = 4.9Hz, C ₃ -H), 6.60-8.05 (m, aromatic H).

The corresponding (3S, 4S) isomer can also be isolated.

IR cm-1: 3280, 1760 and 1100.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.81 (s, OCH ₃ ),

3.27 (s, NH), 3.95 (s, C ₃ -H, C ₄ - H), and 6.70 to 8.00 (m, aromatic H).

Reference Example 43

Under ice-cooling, 0.7 g of (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine To a solution of the (isomer) (syn isomer) in dimethylformamide (4 mL) was added 1.3 mL of 15% aqueous sodium methyl sulfide and the resulting mixture was stirred for 2 hours. Ethyl acetate and water were added to the reaction mixture, and the organic layer was separated, washed with water and evaporated. The residue was purified on a silica gel column using chloroform: ethyl acetate: methanol = 7: 7: 1 (0.377 g) as (3R, 4S) -4-methylthio-3- [2- (2-methylthioacetamidothiazole-4-). yl) -2- (methoxyimino) acetamido] -2-oxoazetidine.

IR .nu ® ^ ^r _x cm⁻¹: 3240.3190, 1752, 1665,

1548, 1290, and 1042.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.17 (s, SCH ₃ ), 3.37 (s, -CH ₂ -), 3.90 (s, OCH ₃ ), 4.67 (d, J = 2Hz, C ₄ -H), 4.71 (dd, J = 2.8Hz, C ₃ - H), 7.36 (s, part XXV), 8.77 (s, NH), 9th , 33 (d, J = 8Hz, NH) and 12.56 (s, NH).

Reference Example 44

Under ice-cooling, a solution of (3S, 4S) -4-acetoxy-3- (tritylamino) -2-oxoazetidine (3.0 g) in methanol (50 mL) was added a solution of sodium azide (0.65 g) in water (5 mL). The reaction mixture was stirred at 40-50 ° C for two hours. The solvent was distilled off under reduced pressure and ethyl acetate was added to the residue. The organic layer was separated, washed with water and evaporated. The residue was purified on a silica gel column using ethyl acetate / n-hexane (1: 1 v / v) to give (3S, 4R) -4-azido-3- (tritylamino) -2-oxoazetidine (1.01 g).

IR spectrum cm- ¹ : 3315, 2102, 1775, 1765 and 1255.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.82 (d,

J = 10Hz, NH), 4.07-4.40 (m, C ₃ -H, C ₄ -H),

6.48 (s, NH) and 6.95-7.50 (m, aromatic H).

Further, 1.52 g of the (3S, 4S) -isomer can be isolated.

IR nu * ® ^{r cm-1:} 3315, 2098, 1765 and 1245th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.93 (s, NH),

3.98 (s, C ₃ -H, C ₄ -H), 6.92 (s, NH) and 7.00-7.57 (m, aromatic H).

Reference Example 45

To a solution of (3S, 4R) -4-azido-3-tritylamino-2-oxoazetidine (0.45 g) in acetone (4 mL) was added with 0.255 g of p-toluenesulfonic acid monohydrate and the resulting mixture was stirred at room temperature for 1 hour. stirred. The solvent was distilled off and the precipitated crystals were washed with diethyl ether. The crystals were then collected by filtration to give 0.33 g of (3S, 4R) -3-amino-4-azido-2-oxoazetidine tosylate salt.

IR spectra? Cm -1 3125, 2870, 2130, 1788, 1763, 1200, 1138 and 1125.

Reference Example 46

To a solution of 1.3 g of (3S, 4S) -4-azido-3- (tritylylamino) -2-oxoazetidine in 15 ml of acetone was added 0.736 g of p-toluenesulfonic acid monohydrate, followed by the procedure described in Reference Example 45. worked. 0.886 g of (3S, 4S) -3-amino-4-azido-2-oxo-azelidine tosylate salt are obtained.

IR spectrum ¹ : 3070, 2110, 1778, 172, 1195, 1122, 1030 and 1010.

Reference Example 47

To a suspension of D-2- (4-ethyl-2,3-dioxolepiperazinecarboxamido) -2-thienylacetic acid (0.565 g) in methylene chloride (20 ml) was added under ice-cooling, 0.189 g of trimethylchlorosilane and 0.176 g of triethylamine. and the resulting reaction mixture at room temperature17

-171

Stir at 189,545 for 30 minutes and then cool to -25 ° C to -20 ° C. To the cooled mixture was added 0.127 g of dimethylformamide and 0.104 g of diphosgene, and the mixture was stirred at the same temperature for 2 hours. At the same time, 0.243 g of pyridine and 2 ml of propylene are added to a suspension of (3S, 4S) -3-amino-4-azido-2-oxoazetidine (0.40 g) in methylene chloride (15 ml) at -25 ° C to -20 ° C. oxide. The resulting solution is then added to the reaction mixture prepared as described above and the resulting mixture is stirred at 0 ° C for one hour. The methylene chloride was then distilled off and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1: 1). 0.546 g of (3S, 4S) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido] -2-oxoazetidine are obtained.

IR spectrum: cm- ¹ : 3270, 2100, 1781, 1708, 1670 and 1500.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.09 (t, J = 7Hz, CH ₃ ), 3.39 (q, J = 7Hz, -CH ₂ -), 3.46-3.68 ( m, -CH ₂ -), 3.84-4.40 (m, -CH ₂ -),

4.59 (dd, J = 2.7Hz, C ₃ -H), 5.08 (d, J = 2Hz, C ₄ -H), 5.74 (d, J = 7 Hz, sub-formula XXVI.)

6.94-7.54 (m, aromatic H), 9.02 (s, NH), 9.24 (d, J = 7Hz, NH) and 9.70 (d, J = 7Hz, NH).

Reference Example 48

To a suspension of D-2- [4-ethyl-2,3-dioxole-piperazinecarboxamido] -2-thienylacetic acid (0.475 g) in methylene chloride (15 ml) was added with ice-cooling, 0.173 g of trimethyl chlorosilane and 0.161 g of triethylamine, followed by the resulting mixture was stirred at room temperature for 30 minutes and then cooled to -25 ° C. Thereafter, 0.116 g of dimethylformamide and 0.095 ml of diphosgene were added, and the reaction mixture was stirred at the same temperature for 2 hours and then cooled to -70 ° C. To the cooled mixture were added, in the order listed, 0.222 g of pyridine, 0.33 g of (3S, 4R) -3-amino-4-azido-2-oxo-azetidine tosylate salt and 2 ml of propylene oxide. The temperature of the reaction mixture was then raised to 0 ° C within one hour with stirring and then stirred at this temperature for one hour. The methylene chloride was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1). 0.337 g of (3S, 4R) -4-azido-3- [2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido] -2-oxoazetidine are obtained.

IR nu * ® ^{r cm-1:} 3270, 2105, 1778, 1710, 1672 and 1,502th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.09 (t, J = 7Hz, CH ₃ ), 3.30-3.68 (m, -CH ₂ -), 3.40 (q, J = 7Hz, -CH ₂ -), 3.77-4.05 (m, -CH ₂ -), 5.02-5.40 (m, C ₃ -H, C ₄ -H), 5.85 (d , J = 8Hz, Part XXVI), 6.93-7.52 (m, aromatic H), 9.03 (s, NH), 9.42 (d, J = 8Hz, NH) and 9.80 (d, J = 8Hz, NH).

'

Reference Example 49

At -10 ° C, to a solution of 0.127 g of dimethylformamide in 5 ml of methylene chloride is added 0.104 ml of diphosgene, and the resulting mixture is stirred at room temperature for 30 minutes and then at -70 ° C is added 15 ml of a methylene chloride solution, containing 0.483 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyimino) acetic acid and 0.176 g of triethylamine. The reaction mixture was stirred at -25 ° C for 2 hours, then cooled to -70 ° C and 0.352 g of triethylamine, 0.40 g of (3S, 4S) -3-amino-4-azido- 2-oxoazetidine tosylate salt and 2 ml propylene oxide. The reaction mixture was then brought to room temperature with stirring over an hour and then ice-cooled for one hour. The precipitated crystals were isolated by filtration (0.383 g of (3S, 4S) -4-azido-3- [2- (2-chloroacetamidothiazol-4-yl) 2- (methoxyimino) acetamido] -2-oxo). azetidine is obtained.

IR .nu ™ ^{r cm-1:} 3265, 2110, 1755, 1678 and 1545th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.90 (s, CH ₃ ), 4.35 (s, -CH ₂ -), 4.70 (dd 1 J = 2.8Hz, C ₃ -H). , 5.13 (d, J = 2Hz, C ₄ -H), 7.45 (s, part XXVII.), 9.13 (s, NH) and 9.44 (d, J = 8Hz, NH) .

Reference Example 50

In the same manner as in Reference Example 49, but starting from 0.40 g of (3S, 4S) -3-amino-4-azido-2-oxoazetidine tosylate salt, 0.375 g of (3S, 4R) -4-azido-3- [2- (2-Chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -2-oxo-azetidine can be prepared.

IR: 3260, 2110, 1768, 1670 and 1540;

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.90 (s, CH ₃ ), 4.35 (s, -CH ₂ -), 5.18-5.40 (m, C ₃ -H, C ₄ --H), 7.34 (s, part XXV.), 9.07 (s, NH) and 9.59 (d, J = 8Hz, NH).

Reference Example 57

Under ice-cooling, a solution of (3S, 4S) -4-acetoxy-3- (trityl-amino) -2-oxoazetidine (4.24 g) in methanol (30 mL) was treated with 15% aqueous sodium methyl sulfide (8.64 mL). and the resulting reaction mixture was stirred at room temperature for one hour. The solvent was evaporated and the residue was dissolved in ethyl acetate and the resulting solution was washed with water. The ethyl acetate was distilled off and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1: 1). Thus 1.43 g of (3R, 4S) -4-methylthio-3- (tritylamino) -2-oxoazetidine (Compound A) and 1.62 g of (3R, 4R) -4-methylthio-3- (trityl) are obtained. -amino) -2-oxoazetidine (compound B) was obtained.

Identification of Compound A:

IR .nu ™ ^{r cm-1:} 3275, and 1750th

-18189 545 dichloromethane on silica gel eluting with ethyl acetate and n-hexane 1; Purification using 1 volume (0.415 g) of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (methylsulfonyl) -2- oxoazetidine. The product was found to be identical to the syn isomer prepared according to Reference Example 15 on the basis of spectral data.

Reference Example 42 To a solution of (3S, 4S) -4-acetoxy-3- (tritylamino) -2-oxoazetidine (g) in methanol (30 mL) was added 1.7 g of zinc acetate and the resulting mixture was refluxed for 30 minutes. . The reaction mixture was concentrated under reduced pressure and ethyl acetate was added to the residue. The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using ethyl acetate / n-hexane (1: 1 v / v) to give (3S, 4R) -4-methoxy-3- (tritylamino) -2-oxoazetidine (0.912 g).

IR Spectrum: ^Rf * cm ^-1 : 3270, 3210, 1772, 1725 and 1097.

NMR (CDC1 _3, ppm): 2.98 (s, _OCH3), 3.01 (d, J = 9Hz, NH), 3.88 (d, J = 4 Hz, C ₄ -H), 4 , 08 (dd, J = 4.9Hz, C ₃ -H), 6.60-8.05 (m, aromatic H).

The corresponding (3S, 4S) isomer can also be isolated.

IR nu ^ ® ^r cm ': 3280, 1760 and 1100th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.81 (s, OCH ₃ ),

3.27 (s, NH), 3.95 (s, C ₃ -H, C ₄ -H) and 6.70-8.00 (m, aromatic H).

Reference Example 43

Under ice-cooling, 0.7 g of (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine To a solution of the (isomer) (syn isomer) in 4 ml of dimethylformamide was added 1.3 ml of a 15% aqueous solution of sodium methylsulfide and the resulting mixture was stirred for 2 hours. Subsequently, ethyl acetate and water were added to the reaction mixture, and the organic layer was separated, washed with water and evaporated. The residue was purified on a silica gel column using chloroform: ethyl acetate: methanol = 7: 7: 1 (0.377 g) as (3R, 4S) -4-methylthio-3- [2- (2-methylthioacetamidothiazole-4-). yl) -2- (methoxyimino) -acetamido] -2-oxoazetidine.

IR spectrum cm- ¹ : 3240, 3190, 1752, 1665,

1548, 1290, and 1042.

NMR (d _e -DMSO, ppm): 2.17 (s, SCH _3), 3.37 (s, - CH ₂ -), 3.90 (s, _OCH3), 4.67 (d, J = 2Hz, C ₄ -H), 4.71 (dd, .1 = 2.8Hz, C ₃ -. H), 7.36 (s, part XXV), 8.77 (s, NH); 9.33 (d, J = 8Hz, NH) and 12.56 (s, NH).

Reference Example 44

Under ice-cooling, a solution of (3S, 4S) -4-acetoxy-3- (tritylamino) -2-oxoazetidine (3.0 g) in methanol (50 mL) was added with a solution of sodium azide (0.65 g) in water (5 mL). The resulting reaction mixture was stirred at 40-50 ° C for two hours. The solvent was distilled off under reduced pressure and ethyl acetate was added to the residue. The organic layer was separated, washed with water and evaporated. The residue was purified on a silica gel column using ethyl acetate / n-hexane (1: 1 v / v) to give (3S, 4R) -4-azido-3- (tritylamino) -2-oxoazetidine (1.01 g).

IR .nu ™ ^{r cm-1:} 3315, 2102, 1775, 1765 and 1255th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.82 (d,

J = 10Hz, NH), 4.07-4.40 (m, C ₃ -H, C ₄ -H),

6.48 (s, NH) and 6.95-7.50 (m, aromatic H).

Further, 1.52 g of the (3S, 4S) -isomer can be isolated.

IR Spectrum ^:? Cm ^-1 : 3315, 2098, 1765 and 1245.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.93 (s, NH),

3.98 (s, C ₃ -H, C ₄ -H), 6.92 (s, NH) and 7.00-7.57 (m, aromatic H).

Reference Example 45

To a solution of (3S, 4R) -4-azido-3-tritylamino-2-oxoazetidine (0.45 g) in acetone (4 mL) was added with 0.255 g of p-toluenesulfonic acid monohydrate and the resulting mixture was stirred at room temperature for 1 hour. stirred. The solvent was distilled off and the precipitated crystals were washed with diethyl ether. The crystals were then collected by filtration to give 0.33 g of (3S, 4R) -3-amino-4-azido-2-oxoazetidine tosylate salt.

R spectrum nu ™ ^{r cm-1:} 3125, 2870, 2130, 1788, 1763, 1200, 1138 and 1125th

Reference Example 46

To a solution of (3S, 4S) -4-azido-3- (tritylamino) -2-oxoazetidine (1.3 g) in acetone (15 mL) was added p-toluenesulfonic acid monohydrate (0.736 g) and the resulting mixture was prepared as described in Reference Example 45. worked. 0.886 g of (3S, 4S) -3-amino-4-azido-2-oxoazetidine tosylate salt is obtained.

IR spectrum:? cm- ¹ : 3070, 2110, 1778, 17 (→ 2, 1195, 1122, 1030 and 1010.

Reference Example 47

Under ice-cooling, a suspension of 0.565 g of L) -2- (4-ethyl-2,3-dioxolepiperazine carboxamido) -2-lienylacetic acid in 20 ml of methylene chloride is added 0.189 g of trimethylchlorosilane and 0.176 g of triethylamine and then the reaction mixture at room temperature17

-191

It was stirred at 189,545 for 30 minutes and then cooled to -25 ° C to -20 ° C. To the cooled mixture was added 0.127 g of dimethylformamide and 0.104 g of diphosgene, and the mixture was stirred at the same temperature for 2 hours. At the same time, 0.243 g of pyridine and 2 ml of propylene are added to a suspension of (3S, 4S) -3-amino-4-azido-2-oxoazetidine (0.40 g) in 15 ml of methylene chloride at -25 ° C to -20 ° C. oxide. The resulting solution is then added to the reaction mixture prepared as described above and the resulting mixture is stirred at 0 ° C for one hour. The methylene chloride was then distilled off and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1). 0.546 g of (3S, 4S) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido] -2-oxoazetidine are obtained.

IR .nu ™ ^{r cm-1:} 3270, 2100, 1781, 1708, 1670 and 1500th

NMR (d _e -DMSO, ppm): 1.09 (t, J = 7Hz, _CH3), 3.39 (q, J = 7 Hz, - CH ₂ -), 3.46-3.68 ( m, -CH ₂ -), 3.84-M, 40 (m, -CH ₂ -),

4.59 (dd, J = 2.7Hz, C ₃ -H), 5.08 (d, J = 2Hz, C ₄ -H), 5.74 (d, J = 7 Hz, sub-formula XXVI.)

6.94-7.54 (m, aromatic H), 9.02 (s, NH), 9.24 (d, J = 7Hz, NH) and 9.70 (d, J = 7Hz, NH).

Reference Example 48

To a suspension of D-2- [4-ethyl-2,3-dioxo-1-piperazinecarboxamido] -2-thienylacetic acid (0.475 g) in methylene chloride (15 ml) was added with ice-cooling, 0.173 g of trimethyl chlorosilane and 0.161 g of triethylamine, then the resulting mixture was stirred at room temperature for 30 minutes and then cooled to -25 ° C. Thereafter, 0.116 g of dimethylformamide and 0.095 ml of diphosgene were added, and the reaction mixture was stirred at the same temperature for 2 hours and then cooled to -70 ° C. To the cooled mixture were added, in the order listed, 0.222 g of pyridine, 0.33 g of (3S, 4R) -3-amino-4-azido-2-oxo-azetidine tosylate salt and 2 ml of propylene oxide. The temperature of the reaction mixture was then raised to 0 ° C within one hour with stirring, and stirring was continued at this temperature for one hour. The methylene chloride was distilled off and the residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1). 0.337 g of (3S, 4R) -4-azido-3- [2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido] -2-oxoazetidine are obtained.

IR .nu ™ _K ^r cm ^-1: 3270,2105,1778, 1710, 1672 and 1,502th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.09 (t, J = 7Hz, CH ₃ ), 3.30-3.68 (m, -CH ₂ -), 3.40 (q, J = 7Hz, -CH ₂ -), 3.77 4.05 (m, -CH ₂ -), 5.02-5.40 (m, C ₃ -H, C ₄ -H), 5.85 (d, J = 8Hz, portion XXVI), 6.93-7.52 (m, aromatic H), 9.03 (s, NH), 9.42 (d, J = 8Hz, NH) and 9.80 ( d, J = 8Hz, NH).

'

Reference Example 49

At -10 ° C, to a solution of 0.127 g of dimethylformamide in 5 ml of methylene chloride is added 0.104 ml of diphosgene and the resulting mixture is stirred at room temperature for 30 minutes and then at -70 ° C is added 15 ml of methylene chloride solution, containing 0.483 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyimino) acetic acid and 0.176 g of triethylamine. The reaction mixture was stirred at -25 ° C for 2 hours, then cooled to -70 ° C and 0.352 g of triethylamine, 0.40 g of (3S, 4S) -3-amino-4-azido- 2-oxoazetidine tosylate salt and 2 ml propylene oxide. The reaction mixture was then brought to room temperature with stirring over an hour and then ice-cooled for one hour. The precipitated crystals were isolated by filtration (0.383 g of (3S, 4S) -4-azido-3- [2- (2-chloroacetamidothiazol-4-yl) 2- (methoxyimino) acetamido] -2-oxo). azetidine is obtained.

IR spectrum cm- ¹ : 3265, 2110, 1755, 1678 and 1545.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.90 (s, CH ₃ ), 4.35 (s, -CH ₂ -), 4.70 (dd, J = 2.8Hz, C ₃ -H ), 5.13 (d, J = 2Hz, C ₄ H), 7.45 (s, part of XXVII), 9.13 (s, NH) and 9.44 (d, J = 8Hz, NH). ).

Reference Example 50

In the same manner as in Reference Example 49, but starting from 0.40 g of (3S, 4S) -3-amino-4-azido-2-oxoazetidine tosylate salt, 0.375 g of (3S, 4R) -4-azido-3- [2- (2-Chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -2-oxo-azetidine can be prepared.

IR .nu ™ ^{r cm-1:} 3260, 2110, 1768, 1670 and 1540th

NMR (d _e -DMSO, ppm): 3.90 (s, _CH3), 4.35 (s, _-CH2 -), 5.18 to 5.40 (m, C ₃ -H, C _4-H), 7.34 (s, part XXV.), 9.07 (s, NH) and 9.59 (d, J = 8Hz, NH).

Reference Example 51

Under ice-cooling, a solution of (3S, 4S) -4-acetoxy-3- (tritylamino) -2-oxoazetidine (4.24 g) in methanol (30 mL) was treated with 15% aqueous sodium methyl sulfide (8.64 mL). and the resulting reaction mixture was stirred at room temperature for one hour. The solvent was evaporated and the residue was dissolved in ethyl acetate and the resulting solution was washed with water. The ethyl acetate was distilled off and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1: 1). Thus 1.43 g of (3R, 4S) -4-methylthio-3- (tritylamino) -2-oxoazetidine (Compound A) and 1.62 g of (3R, 4R) -4-methylthio-3- (trityl) are obtained. -amino) -2-oxoazetidine (compound B) was obtained.

Identification of Compound A:

IR nu = ^B; cm ': 3275 and 1750.

-201

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Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.65 (s, CH ₃ ), 3.00 (broad s, NH), 4.03-4.20 (m, C ₃ -H, C ₄ -H). , 7.01 (s, NH) and 6.80-7.90 (m, aromatic H).

Identification of Compound B:

IR .nu £ f ^r _x cm ^-1: 3260 and 1,752th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.73 (s, CH ₃ ),

2.98 (d, J = 8Hz, NH), 4.15 (d, J = 5Hz, _C4 -H);

4.26 (dd, J = 5.8Hz, C ₃ -H), 6.83 (s, NH) and 7.00-7.80 (m, aromatic H).

Reference Example 52

To a solution of (3R, 4S) -4-methylthio-3- (tritylamino) -2-oxoazetidine (0.9 g) in acetone (5 mL) was added p-toluenesulfonic acid monohydrate (0.503 g) and the mixture was prepared as described in Reference Example 45. worked. 0.69 g of (3R, 4S) -3-amino-4-methylthio-2-oxoazetidine is obtained.

IR spectrum cm- ¹ cm ^-1 : 3100-2900,1798,1770, 1755, 1190, 1165 and 1120.

Reference Example 53

At -10 ° C, to a solution of 0.228 g of dimethylformamide in 5 ml of methylene chloride was added 0.137 ml of diphosgene, and the resulting mixture was stirred at room temperature for 30 minutes and then at -70 ° C was added 15 ml of methylene chloride solution, containing 0.80 g of 2- (2-chloroacetamidothiazol-4-yl) -2 (methoxyimino) acetic acid and 0.316 g of triethylamine. The resulting mixture was then stirred at -25 ° C for 2 hours, then cooled to -70 ° C and 0.632 g of triethylamine, 0.69 g of (3R, 4S) -3-amino-4-methylthio were added in the following order. -2-oxoazetidine tosylate salt and 2 ml propylene oxide. The temperature of the reaction mixture was then raised to 0 ° C over one hour with stirring, followed by stirring at the same temperature for 2 hours. The reaction mixture was concentrated and tetrahydrofuran was added to the residue and the insoluble material was filtered off. The filtrate was evaporated and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: chloroform: methanol = 3: 3: 1). 0.461 g of (3R, 4S) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) acetamido] -4-methylthio-2-oxoazetidine are obtained.

IR: cm- ¹ : 3255, 1758, 1670, 1540, 1270 and 1040.

Nuclear Magnetic Resonance Spectrum (d ₆ DMSO, ppm): 2.14 (s, CH ₃ ),

3.90 (s, OCH 3, 4.35 (s, -CH ₂ -), 4.57-4.90 (m, C ₃ -H, C ₄ -H), 7.40 (s, XXV). part), 8.80 (s, NH), 9.37 (d, J = 9Hz, NH) and 12.88 (broad s, NH).

Reference Example 54

To a suspension of D-2- (4-ethyl-2,3-dioxolepiperazinecarboxamido) -2-thienylacetic acid (0.552 g) in methylene chloride (15 ml) was added 0.2 g of trimethylsilyl chloride and 0.187 g of ice-cooling. triethylamine and the resulting mixture was stirred at room temperature for 30 minutes and then cooled to -25 ° C. Then 0.135 g of dimethylformamide and 0.11 ml of diphosgene are added and the mixture is stirred at the same temperature for a further 2 hours. After cooling to -70 ° C, 0.258 g of pyridine, 0.426 g of (3R, 4S) -3-amino-4-methylthio-2-oxoazetidine tosylate salt and 2 ml of propylene oxide are added in the order listed. The temperature of the resulting reaction mixture was raised to 0 ° C over 30 minutes with stirring and then stirred at this temperature for an additional hour. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography. 0.308 g of (3R, 4S) -3- [2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido] -2-oxoazetidine are obtained.

IR £ spektrumnü _x ^r cm ^- ': 3270.1768, 1710, 1670, 1502 and 1,182th

Reference Example 55

Under ice-cooling, a solution of 5.0 g of (3S, 4S) -4-acetoxy-3- (tritylamino) -2-oxoazetidine in 100 ml of methanol is added 1.6 ml of thiophenol and 15.5 ml of 1 N aqueous sodium hydroxide. hydroxide. The resulting mixture was stirred under ice-cooling for 20 minutes and then at room temperature for an additional 50 minutes. The crystals thus precipitated were isolated by filtration

2.35 g of (3R, 4R) -4-phenylthio-3- (tritylamino) -2-oxoazetidine (Compound A) are obtained. The filtrate was evaporated and the residue was dissolved in ethyl acetate and the resulting solution was washed with water and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain the desired compound (3R, 4S) (Compound B) (2.65g).

Identification of Compound A:

IR .nu ™ ^r cm ^- ': 3290, 1755 and 1725th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.10 (d, J = 8Hz, NH), 4.48-4.83 (m, C ₃ -H, C ₄ -H), 6.08 (s, NH) and 7.17-7.65 (m, aromatic H).

Identification of Compound B:

IR nu * _x cm⁻¹: 3300-3220 and 1755th

NMR (CDC1 _3, ppm): 2.87 (d, J = 8Hz, NH), 4.00 (dd, J = 2.9Hz, C ₃ -H), 4.37 (d, J = 2Hz , C ₄ -H), 6.52 (s, NH) and 7.10-7.70 (m, aromatic H).

Reference Example 56

Under ice-cooling, a solution of (3R, 4R) -4-phenylthio-3-tritylamino-2-oxoazetidine (1.5 g) in acetone (20 ml) was treated with p-toluenesulfonic acid monohydrate (0.72 g) and the resulting mixture and processed as described in Reference Example 45. 1.25 g of (3R, 4R) -3-amino-4-phenylthio-2-oxoazetidine tosylate salt are obtained.

IR nu ^ cm ^- ': 3090,2850,2740,1780, 1205, 1175 and 1118th

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Reference Example 57

To a solution of (3R, 4S) -4-phenylthio-3-tritylamino-2-oxoazetidine (2.65 g) in acetone (20 ml) was added 1.27 g of p-toluenesulfonic acid monohydrate and the resulting mixture was stirred at room temperature for 2 hours. It is processed as described in Reference Example 45. so

1.9 g of (3R, 4S) -3-amino-4-phenylthio-2-oxo-azelidine tosylate salt are obtained.

R spectrum nu ™ ^{r cm-1:} 3240, 3140, 3050, 2980, 2920, 1807, 1210, 1200, 1168, 1128th

Reference Example 58

In the same manner as in Reference Example 49, but using 0.19 g of dimethylformamide, 0.156 ml of diphosgene, 0.732 g of (3R, 4S) -3-amino-4-phenylthio-2-oxoazetidine tosylate salt and 2 ml of propylene oxide. g of (3R, 4S) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4-phenylthio-2-oxo-azetidine is obtained.

I R spectrum nu ™ ^r cm⁻¹: 3240, 3170, 3055, 1752, 1652 and 1535th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.90 (s, CH 3), 4.37 (s, -CH ₂ -), 4.69 (dd, J = 2.8Hz, C ₃ -H). 4.98 (d, J = 2Hz, C ₄ - H), 7.34 (. s, part formula XXVI), 7.30-7.60 (m, aromatic H), 9.04 (s, NH ), 9.38 (d, J = 8Hz, NH) and 12.84 (s, NH).

Reference Example 59

In the same manner as in Reference Example 54, but 0.57 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetic acid, 0.212 g of trimethylchlorosilane, 0.143 g of dimethyl- formamide, 0.193 g of diphosgene, 0.273 g of pyridine, 0.55 g of (3R, 4S) -3 salt of (3R, 4S) -3-amino-4-phenylthio-2-oxoazetidine tosylate and 2 ml of propylene oxide. [2- (4-Ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4-phenylthio-2-oxoazetidine is obtained.

IR .nu ™ ^r cm '': 3270, 1772, 1710, 1670 and 1,502th

purification using a 1: 1 by volume mixture of ethyl acetate and n-hexane as eluent. 0.960 g of (3R, 4R) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido] -4-methylthio-2-oxoazetidine are obtained. .

IR .nu ™ ^r cm '': 1760, 1710,1673,1500, 1130th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 4Hz, CH ₃ ), 1.73 (s, CH ₃ ), 3.53 (m, --CH ₂ -), 4, 00 (m, -CH ₂ -), 4.83 (d, J = 4Hz, C ₄ -H), 5.30 (dd, J = 4.6Hz, C ₃ -H), 5.93 (d, J = 4Hz, part XXVI), 6.90-7.63 (m, aromatic H), 8.90 (s, NH), 9.36 (d, J = 6Hz, NH), and 9.83 (m). d, J = 4Hz, NH).

Reference Example 61

To a solution of 2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetic acid (0.833 g) in triethylamine (0.304 g) in methylene chloride (20 ml) was added 0.625 g of powdered phosphorus pentachloride under ice-cooling. the resulting mixture was stirred for one hour. The mixture was concentrated under reduced pressure, and the residue was washed with n-hexane and dissolved in tetrahydrofuran. After filtering off the insoluble material, the filtrate was added under ice-cooling to a solution of (3R, 4R) -3-amino-4-methylthio-2-oxoazetidine-p-toluenesulfonate (0.913 g) and triethylamine (0.910 g) in tetrahydrofuran (15 mL). The reaction mixture was stirred at room temperature for 1 hour, then filtered and the filtrate was concentrated under reduced pressure. The residue is washed first with aqueous sodium bicarbonate solution, then with water and then dried. 0.780 g of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2-methoxyimino) acetamido] -4-methylthio-2-oxoazetidine are obtained.

IR nu ^ ^cm-1: 1760, 1660, 1545 and 1050th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.06 (s, SCH ₃ ), 3.90 (s, OCH 3), 4.36 (s, -CH ₂ -), 4.93 (d, J = 4Hz, C ₄ -H), 5.40 (dd, J = 4.6Hz, C ₃ -H), 7.50 (s, moiety XXVI), 8.84 (broad s, NH),

9.53 (d, J = 6Hz, NH) and 12.90 (broad s, NH).

Reference Example 60

Under ice-cooling, to a solution of 0.976 g of D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetic acid and 0.304 g of triethylamine in 20 ml of methylene chloride is added 0.625 g of powdered phosphorus pentachloride. the resulting mixture was stirred at the same temperature for one hour. The mixture was concentrated under reduced pressure, and the residue was washed with n-hexane and dissolved in tetrahydrofuran. After filtration of the insoluble matter, a solution of 0.913 g of (3R, 4R) -3-amino-4-methylthio-2-oxoazetidine-p-toluenesulfonate and 0.910 g of triethylamine in 15 ml of tetrahydrofuran was added to the filtrate under ice-cooling. The resulting reaction mixture was stirred at room temperature for 1 hour and then filtered. The filtrate was evaporated and the residue chromatographed on a silica gel column

Reference Example 62

Under ice-cooling, to a solution of 0.608 g of (3R, 4R) -4-methylthio-2-oxoazetidine-p-toluenesulfonate and 0.380 g of pyridine in 10 ml of methylene chloride is added 0.581 g of 3- (2,6-dichlorophenyl) - A solution of 5-methyl-4-isoxazolylcarbonyl chloride in methylene chloride (5 mL) was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1: 1). 0.550 g of (3R, 4R) -3- [3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarboxamido] -4-methylthio-2-oxoazetidine are obtained.

IR .nu ™ ^r cm⁻¹: 1760, 1660, 1595 and 1500th

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Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.90 (s, CH ₃ ),

2.83 (s, CH ₃ ), 4.70 (d, J = 4Hz, C ₄ -H), 5.50 (dd, J = 4.8Hz, C ₅ -H), 6.13 (d, J = 8 Hz, NH), 6.50 (broad s, NH) and 7.40 (s, aromatic H).

Reference Example 63

To a solution of (3R, 4R) -4- (methylsulfonyl) -3- (tritylamino) -2-oxoazetidine (0.4 g) in dimethylformamide (2 mL) was added 0.590 g of tetra (n-butyl) ammonium fluoride, and the resulting mixture was stirred at room temperature for 30 minutes. Ice water and ethyl acetate were added to the reaction mixture, and the ethyl acetate layer was separated, washed with water and evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1: 1). 0.282 g of (3R) -4-fluoro-3- (tritylamino) -2-oxoazetidine are obtained.

IR spectrum cm ^-1 : 1765, 1480, 1440, 1300, 750 and 695.

Reference Example 64

To a solution of (3S) -4-fluoro-3- (tritylamino) -2-oxoazetidine (3.3 g) in acetone (10 mL) was added p-toluenesulfonic acid monohydrate (1.82 g) and the reaction mixture prepared in Reference Example 45. . 2.67 g of (3R) -3-amino-4-fluoro-2-oxoazetidine-p-toluenesulfonate are obtained.

IR spectrum:? 1 H / cm -1 ¹ : 1790, 1170, 1035 and 1010.

Reference Example 65

In the same manner as in Reference Example 36, using a reaction mixture of 2.7 g of (3S, 4S) -4-acetoxy-3- (trityl-amino) in a solution of 0.965 g of 5-mercapto-1-methyltetrazolium sodium salt in 10 ml of methanol. ) Was added to a solution of 2-oxo-azetidine in 30 mL of methanol to give 0.70 g of (3R, 4R) -4- (1-methylH-tetrazol-4-ylthio) -3- (trityl-amino) ) -2-oxoazetidine (Compound A) and 1.32 g of the corresponding (3R, 4S) isomer (Compound B) are obtained.

Identification of Compound A:

IR nu "® ^{r cm-1:} 3300, 1779.1728 (sh)

1442, 1340, 1331 and 700.

NMR (CDC1 _3, ppm): 3.75 (s, _CH3), 4.93 (q, J = 4 ~ 12 Hz, _C3 -H), 5.85 (d, J = 8Hz, C ₄ -H), 6.59 (bs, NH) and 7.0-7.6 (m, aromatic H).

Identification of Compound B:

IR .nu ™ ^{r cm-1:} 3320,1774,1441,1367, 1225, 1030 and 698th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 3.72 (s, CH ₃ ), 5.04 (bs, C ₃ -H), 5.37 (d, J = 2Hz, C ₄ -H), δ , 72 (broad s, NH) and 7.0-7.6 (m, aromatic H).

Reference Example 66

To a solution of 0.535 g of (3R, 4R) -4- (1-methyl-1H-tetrazol-4-ylthio) 3- (tritylamino) -2-oxoazetidine in 5 ml of acetone was added 0.230 g of p-toluenesulfonic acid monohydrate and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated and the residue was washed with diethyl ether and dissolved in 15 ml of tetrahydrofuran.

At the same time, as described in Reference Example 61, 0.336 g of 2- (2-chloroacetamidothiazol-4-yl) -2-methoxyimino) acetic acid was treated with phosphorus pentoxide to give a solution of the corresponding acid chloride in 10 ml of tetrahydrofuran. The solution thus prepared is then added under ice-cooling to a solution obtained by mixing the solution described in the preceding paragraph with 0.270 g of triethylamine. Ethyl acetate was added to the reaction mixture, which was washed with water and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: chloroform: methanol = 3: 3: 1). Thus, 0.380 g of (3R, 4R) 3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (1-methyl-1H-tetrazole-4-) are obtained. il-thio) 2-oxo-azetidine is obtained.

IR spectrum cm- ¹ : 3220, 1790, 1679, 1540, 1365, 1332, 1045.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.72 (s, CH ₃ ), 3.37 (s, CH ₃ ), 4.35 (s, -CH ₂ -), 5.73 (dd, J = 4.8Hz, C ₃ -H), 6.38 (d, J = 4Hz, _C4 -H), 7.23 (s, XXVII, sub-formula), 9.20 (br s, NH); 9.50 (d, J = 8Hz, NH) and 12.84 (broad s, NH).

Reference Example 67

Referring to Reference Example 66, but 1.12 g of (3R, 4S) -4- (1-methyl-1H-tetrazol-4-ylthio) -3- (tritylamino) -2-oxoazetidine Starting from a solution of 5 ml of acetone, 0.491 g of p-toluenesulfonic acid monohydrate and 0.788 g of 2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetic acid, 0.650 g of (3R, 4S) -3- [2 - (2-Chloroacelamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4- (1-methyl-1H-thiazol-4-yl-thio) -2-oxo-azetidine is obtained. .

IR .nu ™ ^r cm⁻¹: 3250, 1787, 1670, 1540, 1365, 1038 and 820th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.88 (s, CH ₃ ), 3.92 (s, CH ₃ ), 4.36 (s, -CH, -), 5.38 (dd, J = 2.8Hz, C ₃ -H), 6.22 (d, J = 2Hz, C ₄ - H), 7.43 (s, part XXV), 9.40 (s, NH), 9th , 51 (d, J = 8Hz, NH) and 12.84 (broad s, NH).

Reference Example 68

To a solution of 1.13 g of 2- (1-carboxyisopropoxyimino) -2- (2-tritylaminothiazol-4-yl) acetic acid in 15 ml of methylene chloride is added 0.454 g of dicyclohexylcarbodiimide (hereinafter: the compound will be referred to as DCC) and then the resulting mixture at room temperature for 20 minutes.

-231

189,545 and then filtered to remove insoluble material.

At the same time, (3S, 4S) -3-amino-4-azido-2-oxoazetidine (0.598 g) was suspended in methylene chloride (10 ml), and pyridine (0.159 g) and dimethylformamide (10 ml) were added to the resulting suspension under ice-cooling. To the resulting solution was added the filtrate prepared as described in the previous paragraph, and the resulting reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: chloroform: methanol = 3: 1: 1). 0.63 g of (3S, 4R) -4-azido-3- {2 - [(2-tritylaminothiazol-4-yl) carboxymethyliminino] -2-methylpropionamido} -2-azetidinone is obtained. .

IR spectrum nü *? _x ^{r cm-1:} 3400-3200, 2105, 1768 and 1600, the 1520th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.36 (s, CH 3), 1.41 (s, CH 3, 4.49 (dd, J = 2.8Hz, C ₃ H),

4.96 (d, J = 2Hz, C ₄ -H), 6.73 (s, Part XXV.), 7.14 to 7.55 (m, aromatic H), 8.94 (s, 4 NH) and

9.88 (d, J = 8Hz, NH).

Reference Example 69

0.615 g of 2- [1- (2-trimethylsilyl-ethoxycarbonyl) -isopropoxyimino] -2- (2-trityl-aminothiazol-4-yl) -acetic acid, 0.180 g of N-hydroxy-5-norbornene- A mixture of 2,3-dicarboximide and 0.210 g of DCC in 6 ml of methylene chloride was stirred at room temperature. The precipitate was filtered off and the filtrate was first filtered with 0.305 g of (3R, 4R) -3-amino-4-methylthio-2-oxoazetidine-p- toluene sulfonate and then a solution of 0.105 g of triethylamine in 10 ml of methylene chloride are added. After stirring for 4 hours, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: chloroform: n-hexane = 2: 2: 1). Thus, 0.40 g of (3R, 4R) -3- {2- [1- (2-trimethylsilyl-ethoxycarbonyl) -isopropoxyimino] -2- (2-trityl-aminothiazol-4-yl) is obtained. -acetamido} -4-methylthio-2-oxoazetidinone is obtained.

IR spectrum? _x ^{r cm-1:} 1760, 1670 and 1520. NMR (d ₆ -DMSO, ppm): 0.03 (s,

CHJ, 0.9 (t, J = 8Hz, _-CH2 -), 1.5 (s, CHJ, 2.10 (s, CHJ, 4.90 (d, J = 4 Hz, C ₄ - H); 5.40 (dd, J = 4.8Hz, C ₃ -H) and 7.0-7.6 (m, aromatic H).

Reference Example 70

1. To a solution of (3S, 4S) -4-acetoxy-3- (trityl-amino) -2-oxoazetidine (1.93 g) in methanol (100 mL) is added, while cooling with ice, 0.64 g of the methyl ester of thioglycolic acid. After 1 hour, the solvent was distilled off and the residue was dissolved in ethyl acetate. The resulting solution was washed with water, evaporated and the residue was purified by silica gel column chromatography (eluent: methylene chloride: ethyl acetate = 11: 1). There were thus obtained 1.38 g of 22 (3R, 4R) -4- (methoxycarbonylmethylthio) -3- (tritylamino) -2-oxoazetidine (Compound A) and 0.92 g of the corresponding (3R, 4S) isomer (compound B).

Identification of Compound A:

IR nu * ® ^{r cm-1:} 3310, 1760, 1730, 1487, 1445, 1240, 1152, 700th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.86, 3.08 (ABq, J = 15Hz, -CH ₂ -), 3.61 (s, CH ₂ ), 2.98 (d, J = 9Hz, NH), 4.42 (dd, J = 6.9Hz, C ₃ -H), 4.43 (d, J = 6Hz, C ₄ -H), 6.67 (s, NH) and 6.8-. 7.5 (m, aromatic H).

Identification of Compound B:

IR Spectrum: cm ^-1 : 1760, 1730, 1275, 1150 and 697.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.93 (bs, -CH ₂ -), 3.57 (s, CH 3, 3.94-4.2 (m, C ₃ -H, C _4). -H), 6.55 (broad s, NH) and 6.8-7.5 (m, aromatic)

H).

2. Dissolve 0.59 g of the (3R, 4R) -trityl derivative obtained in Step 1 in 3 ml of acetone and add 0.251 g of p-toluenesulfonic acid monohydrate to the resulting solution. The reaction mixture was stirred at room temperature for 1 hour and then the solvent was distilled off to give (3R, 4R) -3-amino-4- (methoxycarbonylmethylthio) -2-oxoazetidine.

To a solution of the product prepared as described in the previous paragraph under stirring and ice-cooling, is added 0.388 g of sodium bicarbonate in 20 ml of water and 15 ml of tetrahydrofuran, followed by 0.571 g of 2- (2-chloroacetamidothiazol-4-yl) -2 - (methoxyimino) acetyl chloride hydrochloride. During the latter addition, the pH of the reaction mixture is maintained between 7 and 8 by the addition of sodium bicarbonate as needed. After the addition was complete, the reaction mixture was stirred for 30 minutes and then extracted with ethyl acetate. The solvent was evaporated and the residue was purified by silica gel column chromatography (eluent: ethyl acetate: chloroform: methanol = 4: 4: 1). 0.50 g of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (methoxycarbonylmethylthio) is thus obtained. -2-oxoazetidine is obtained.

IR .nu ™ ^{r cm-1:} 3252.1762, 1745.1663, 1540, 1160 and 1,052th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.46 (s, -CH ₂ -), 3.68 (s, CH 3), 3.89 (s, CH 3, 4.37 (s, C ₁ -CH ₂ -). , 5.09 (d, J = 4Hz, C ₄ -H), 5.40 (dd, J = 4.8Hz, C ₃ -H), 7.48 (s, part of Formula XXV),

8.80 (bs, NH), 9.50 (d, J = 8Hz, NH) and 12.86 (bs, NH).

Reference Example 71

(3R, 4S) -3- [2- (2-Chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (methoxycarbonylmethylthio) can be prepared as described in Reference Example 70. -2-azetidinone.

IR nu ^ ^{r cm-1:} 3252,1763,1735,1660, 1540, 1278 and 1160th

NMR (d _e -DMSO, ppm): 3.56 (s,

-241

189 545 -CH ₂ -), 3.68 (s, _CH3), 3.91 (s, _CH3), 4.36 (s, C1CH ₂ -), 4.75 (dd, J = 2.8Hz , C ₃ -H), 4.82 (d, J = 2Hz, C ₄ -H), 7.41 (s, moiety XXV), 8.81 (s, NH), 9.36 (d, J = 8Hz, NH) and 12.38 (broad s, NH).

Reference Example 72

1. (3R, 4R) -3- [2- (2-Chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4- (1R, 4R) -3- n-butylthio) -2-azetidinone.

IR spektrumnü, ^cm-1: 3255, 1758, 1660, 1540. NMR spectrum (d ₆ -DMSO, ppm): 0.88 (m,

CH ₃ ), 1.46 (m, -CH ₂ -), 2.56 (t, J = 7Hz, -CH ₂ -), 3.89 (s, CH ₃ ), 4.34 (s, -CH ₂ -), 4.98 (d, J = 5Hz, C ₄ --H), 5.38 (dd, J = 5.9Hz, C ₃ --H),

7.49 (s, portion XXV), 8.81 (s, NH) and 9.47 (d, J = 9Hz, NH).

2. The corresponding (3R, 4S) -isomer can be prepared as described in Reference Example 70.

IR Spectrum:? Cm ^-1 : 3265.1762, 1660.1540. Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 0.89 (t,

J = 7Hz, _CH3), 1.48 (m, - CH ₂ -), 2.65 (t, J = 7Hz, _-CH2 -), 3.91 (s, _CH3), 4.37 ( s, -CH ₂ -), 4.68 (dd, J = 2.9Hz, C ₃ -H), 4.68 (d, J = 2Hz, C ₄ -H), 7.40 (s, XXV. ), 8.81 (s, NH) and 9.34 (d, J = 9Hz, NH).

Reference Example 73

1. (3R, 4R) -3- (2- (2-Chloroacetamido-thiazol-4-yl) -2- (methoxy-imido) -acetamido] -4-isopropylthio may be prepared as described in Reference Example 70. -2-azetidinone.

IR nu ^ ^{r cm-1:} 3250, 1760, 1660, 1540 and 1050th

NMR (d _e -DMSO, ppm): 1.20 and 1.25 (both d, J = 6Hz, _CH3), 3.06 (m, part formula XXVI.), 3.88 (s, CH ₃ ), 4.35 (s, C ₁ -C ₂ -), 5.06 (d, J = 5Hz, C ₃ -H), 5.41 (dd, J = 5.9Hz, C ₄ -H),

7.46 (s, portion XXV), 8.74 (broad s, NH), 9.36 (d, J = 9Hz, NH), and 12.86 (broad s, NH).

2. By following the procedure described in Reference Example 70, the corresponding (3R, 4S) -isomer is prepared.

IR .nu ® ^ ^{r _l} cm: 3275,1760,1689,1660, 1580, 1542, 1365, 1322 and 1045th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.28 (d, J = 7Hz, CH ₃ ), 3.15 (m, moiety XXVI), 3.90 (s, CH ₃ ), δ 37 (s, C ₁ -C ₂ -), 4.68 (dd, J = 2.8Hz, C ₃ -H), 4.74 (d, J = 2Hz, C ₄ -H), 7.39 (s, XXV ), 8.83 (s, NH), 9.35 (d, J = 8Hz, NH) and 12.88 (broad s, NH).

Reference Example 74

By following the procedure described in Reference Example 70, (3R, 4S) -3- [2- (2-Chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (n-propylthio) is obtained. thiocarbonyl) thio-2-azetidinone.

IR spectrum cm- ¹ : 3250, 1770, 1662, 1540, 1263, 1043.

NMR (d _e -DMSO, ppm): 1.97 (t, J = 7Hz, _CH3), 1.70 (m, _-CH2 -), 3.39 (t, J = 7Hz, -CH ₂ -), 3.90 (s, CH ₃ ), 4.36 (s, C ₁ - CH ₂ -), 5.05 (dd, J = 2.8Hz, C ₃ --H), 5.73 (d, J = 2Hz, C ₄ -H), 7.40 (s, part XXV.) and

12.8 (bs, NH).

Example 75:

1. The preparation of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4-cyclohexylthio is prepared as described in Reference Example 70. -2-azetidinone.

IR spectrum: ν cm ^-1 : 1765, 1665, 1545 and 1050.

NMR (d ₆ -DMSO, ppm): 1.0-2.0 (m, _-CH2 -), 3.90 (s, _CH3), 4.36 (s, C1CH ₂ -), 5 10 (d, J = 4 Hz, C ₄ - H), 5.40 (dd, J = 4.8Hz, C ₃ -H), 7.48 (s, part XXV.), 8.76 (br s, NH) and

9.42 (d, J = 8Hz, NH).

2. The corresponding (3R, 4S) -isomer can be prepared as described in Reference Example 70.

IR nu ^ ^r cm⁻¹: 1760, 1660, 1540 and 1040th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.0-2.1 (m, -CH ₂ -), 3.90 (s, CH ₃ ), 4.36 (s, CICH ₂ -), δ , 66 (dd, J = 2.8Hz, C ₃ H), 4.74 (d, J = 2Hz, C ₄ -H),

7.38 (s, part of Formula XXV), 8.80 (s, NH) and 9.36 (d, J = 8Hz, NH).

Reference Example 76

3- (Benzyloxycarboxamido) -4-ethoxy-3-methoxy-2-oxo-azetidine can be prepared as described in Reference Example 1.

IR spectrum cm- ¹ : 3275.1780, 1690.1495,

1120th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.15 (t, J = 7Hz, CH ₃ ), 3.48 (s, CH ₃ ), 3.62 6q, J = 7Hz, -CH ₂ -) , 4.91 (s, C ₄ -H), 5.14 (s, -CH ₂ -),

5.88 (s, NH), 7.30 (s, NH) and 7.30 (s, aromatic H).

Example 77:

To a stirred solution of (3S, 4S) -4-acetoxy-3- (tritylamino) -2-oxoazetidine (1.4 g) in methanol (30 mL) was added 0.51 g of sodium salt of N-acetyl cysteamine in 30 mL of methanol. solution. After 30 minutes, the solvent was distilled off and the residue was dissolved in ethyl acetate. The solution was washed with water and evaporated to give 1.6 g of 4- (2-acetamidoethylthio) -3 (tritylamino) -2-oxoazetidine. This was then dissolved in acetone (10 mL), and p-toluenesulfonic acid monohydrate (0.682 g) was added to the resulting solution and the resulting mixture was stirred for 45 minutes. The acetone was then distilled off and the precipitate was filtered off and washed with diethyl ether to give 3-amino-4- (2-acetamidoethylthio) -2-oxoazetidine-p-toluenesulfonate.

This product was then dissolved in 20 mL water and 20 mL

-251

Sodium hydrogen carbonate (0.904 g) was added to a mixture of THF (189,545 mL). While the pH of the mixture is maintained with sodium bicarbonate between 7 and 8 by adding, as necessary, was added 1.432 g of 2- (2-acetates ⁵ mido-thiazol-4-yl) -2- (methoxyimino) acetyl chloride hydrochloride.

After the addition was complete, the reaction mixture was stirred for 30 minutes and then extracted with ethyl acetate.

The extract was washed with water and the solvent evaporated ^10. Diethyl ether was added to the residue, and the precipitated solid was filtered off. 1.5 g of (3R) -4- (2-acetamidoethylthio) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxo are thus obtained. -azetidine is obtained. ⁵

IR spectrum cm- ¹ : 3370, 3270, 1735, 1650, 1530, 1360, 1270 and 1040.

NMR (d ₆ -DMSO, ppm): 1.82, 1.84 (s, _CH3), 2.68 (m, - CH ₂ -), 3.89, 3.91 (each s, ₂₀ CH), 4.40 (s, C1CH ₂ -), 4.74 (d, J = 2Hz, C ₄ -H);

5.02 (d, J = 5Hz, _C4 -H), 4.67 (dd, J = 2.8Hz, C ₃ -H) and 5.37 (dd, J = 5.8Hz, C ₃ -H ), 7.40 and 7.48.

Reference Example 78

Under ice-cooling was added 0.952 g of thionyl chloride, 0.8 g of D-2-thienyl-2-ureidoecetsav suspended in 12 ml of acetonitrile, and the resulting mixture was stirred for 10 minutes and then evaporated ^30th The precipitated crystals were collected by filtration.

0.598 g of (3S, 4R) -3-amino-4-azido-2-oxo-azetidinp-toluenesulfonate in 20 ml of methylene chloride »Qpszuszpenziójához - 70 ° C, the bullet ³ Holies Sequencer added 0.64 g of pyridine, 2 ml of propylene oxide, the crystals prepared as described in the previous paragraph and 10 ml of dimethylformamide. The resulting reaction mixture was stirred at 0 ° C for 3 hours and then concentrated. The residue was purified by chromatography on a silica gel ⁴⁰ column using ethyl acetate and n-hexane using 2: 1 as the eluant. 0.55 g of (3S, 4R) -4-azido-3- (D-2-thienyl-2-ureidoacetamido) -2-oxoazetidine is obtained. ⁴⁵

IR .nu ™ ^{r cm-1:} 3260.2110, 1770, 1650, 1535th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 5.10 5.40 (m, C ₃ -H, C ₄ -H), 5.69 (d, J = 8Hz, part of Formula XXVI), δ, 73 (s, NH ₂ ), 6.76 (d, J = 8 Hz, NH), ⁵⁰

6.90-7.60 (m, aromatic H), 8.99 (s, NH) and 9.25 (d,

J = 8Hz, NH).

Reference Example 79

(3R, 4S) -3- [D-2- (2-Oxo-imidazolidin-1-ylcarboxamido) -2-phenylacetamido] -4-phenylthio-2-oxoazetidine can be prepared as described in Reference Example 54. ⁶³

IR spectrum: cm- ¹ : 3255, 1775, 1695, 1665, 1505, 1480 and 1268.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.19-3.43 (m, -CH ₂ -), 3.62-3.84 (m, -CH ₂ -), 4.56 (dd, "J = 2.9Hz, C ₃ -H), 4.83 (d, J = 2Hz, C ₄ -H), 5.39 ⁶⁵ 24 (d, J = 8Hz, Fibrex XXVI), 7.33 (s, aromatic H), 7.36 (s, aromatic H), 7.55 (s, NH), 8.95 (s, NH), 9.03 (d, J = 8Hz, NH) and 9, 19 (d, J = 9Hz, NH).

Reference Example 80

(3S, 4S) -4-Azido-3- [D-2- (2-oxo-imidazolidin-1-ylcarboxamido) -2-phenylacetamido] -2-oxo-azetidine can be prepared as described in Reference Example 54. .

IR .nu ™ ^{r cm-1:} 3300-3240,2090,1772, 1705, 1660, 1505 and 1255th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.10-3.40 (m, -CH ₂ -), 3.60-3.88 (m, -CH ₂ -), 4.64 (dd, J = 2.8Hz, C ₃ -H), 5.02 (d, J = 2Hz, C ₄ -H), 5.42 (d, J = 8Hz, part formula XVI.), 7.36 (s, aromatic H),

7.54 (s, NH), 8.98 (s, NH) and 9.00-9.20 (m, NH).

Reference Example 81

0.405 g of (3 S, trans) -3-methoxy-4-methylthio-3- (4-nitro-benzyloxycarboxamido) -2-oxo-azetidine-1 (alpha-isopropylidene) -acetic acid methyl ester are 7.5 ml of pyridine and 0, A solution of 5 ml of water was treated with 0.283 g of potassium permanganate to give 0.096 g of (3S, trans) -3-methoxy-4-methylthio-3- (4-nitrobenzyloxycarboxamido) -2-oxoazetidine.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 2.10 (s, CH ₃ ),

3.51 (s, CH ₃ ), 4.72 (s, C ₄ -H), 5.29 (s, -CH ₂ -),

6.22 (s, NH), 6.98 (s, NH), 7.55 and 8.17 (both d, J = 9Hz, aromatic H).

Reference Example 82

(3S, Trans) -3- [D-2- (4-Cyclohexyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -3-methoxy-4 may be prepared as described in Reference Example 16. methylthio-2-azetidinone.

IR woman from a x ^{B r cm-1:} 3270.2925, 1770, 1705, 1670, 1500 and 1170th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 1.94 (s, CH ₃ ),

3.39 (s, CH ₃ ), 4.68 (s, C ₄ -H), 5.57 (d, J = 7Hz, Part XXVI), 3.3-4.1 (m, -CH _2- ), 6.95 (s, NH), 7.2-7.6 (m, aromatic H), 7.50 (s, NH) and 9.84 (d, J = 7Hz, NH).

Reference Example 83

(3S, 4S) -4-Azido-3- [D-2- (3-methyl-3-methylcarbamoyl / -1-ureido) -2-phenylacetamido] is prepared as described in Reference Example 54. 2-azetidine.

IR spectra: cm- ¹ : 3275, 2100, 1700, 1675 and 1495.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.67 (d, J = 4Hz, CH ₃ ), 3.08 (s, CH ₃ ), 4.55 (m, C 1 H), δ 00 and 5.02 (both d, J = 2Hz, C ₄ -H), 5.37 (d, J = 7 Hz, sub-formula XXVI.), 7.36 (s, aromatic H);

8.98 (s, NH), 9.07 (d, J = 8Hz, NH), 9.87 and 9.92 (both d, J = 7Hz, NH).

-261

189,545. Reference Example 84

1. (3S, 4R) -4-Azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S) - can be prepared as described in Reference Example 54. formiloxibutilamido] -2-azetidinone.

IR: 3270.2102, 1772, 1703, 1665, 1510 and 1175.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.11 (t, J = 7Hz, CH ₃ ), 1.25 (d, J = 6Hz, CH ₃ ), 3.42 (q, J = 7Hz, -CH ₂ -), 3.58 (m, _-CH2 -), 3.94 (m, - CH ₂ -.), 4.67 (dd, J = 4.8Hz, partial formula XXVI), 5.14 ( m, C ₃ -H), 5.30 (d, J = 4Hz, C ₄ -H),

5.36 (m, part of Formula XXVI), 8.18 (s, CHO), 9.04 (s, NH), 9.14 (d, J = 8Hz, NH) and 9.39 (d, J). = 8Hz, NH).

2. The corresponding (3S, 4S) isomer can be prepared as described in Reference Example 54.

IR nu ^ ®, ^r, cm ^"1: 3275, 2110, 1782, 1715,

1670,1515,1180.

NMR (d _e -DMSO, ppm): 1.11 (t, J = 7Hz, _CH3), 1.23 (d, J = 6Hz, CH _3), 3.330 to 3.70 (m, -CH ₂ -), 3.42 (q, J = 7Hz, --CH ₂ -), 3.88-4.08 (m, --CH ₂ -), 4.50-4.67 (m, C ₃ -H , Part XXVI), 5.02 (d, J = 1Hz, C ₄ H), 5.26-5.52 (m, part XXVI), 8.19 (s, CHO),

8.99 (s, NH), 9.02 (d, J = 8Hz, NH) and 9.39 (d, J = 8Hz, NH).

Reference Example 85

3- [2- (2-Chloroacetamido-thiazol-4-yl) -2-methoxy-imino) -acetamido] -4-fluoro-2-oxo-azetamide can be prepared as described in Reference Example 54.

IR nu ^ ^cm-1: 1780, 1670, 1540, 1300 and 1040th

Reference Example 86

(3R, 4R) -3- [D-2- (4-Ethyl-2,3-dioxo-piperazine-carboxamido) -2- (chloromethyl) -acetamido] -4 methylthio-2-azetidinone.

IR spectra: cm ^-1 : 1750, 1710, 1670, 1510, 1180.

Reference Example 87

(3R, 4R) -4- (tert-Butylthio) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (S) can be prepared as described in Reference Example 54. ) formyloxy-butylamido] -2-azetidinone.

IR: New cm ^-1 : 3270.1765, 1710, 1672, 1512 and 1188.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 0.87 (m, CH ₃ ), 1.09 (t, J = 7Hz, CH ₃ ), 1.25 (d, J = 7Hz, CH ₃ ), 1.77 (m, _-CH2 -), 2.48 (t, J = 8Hz, _-CH2 -), 3.42 (q, J = 7Hz, _-CH2 -), 3.60 (m, -CH ₂ -), 3.95 (m, -CH ₂ -), 4.74 (dd, J = 5.9Hz, portion of Formula XXVI), 4.92 (d, J = 5Hz, C ₄ -H ), 5.26 (m, _C3 -Η part formula XXVI.)

8.18 (s, CHO), 8.84 (s, NH), 9.10 (d, J = 9Hz, NH) and 9.45 (d, J = 9Hz, NH).

Reference Example 88

(3S, 4R) -4-Azido-3- [D-2- (2-oxoimidazolidin-1-ylcarboxamido) -2-phenylacetamido] -3 (S) was prepared as described in Reference Example 54. ) -formiloxi-butylamido] -2-azetidinone.

IR spectrum cm-1: 3260.2105, 1775, 1722, 1705, 1665, 1518, 1265.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.10-3.50 (m, -CH ₂ -), 3.60-3.90 (m, -CH ₂ -), 5.19 (m, C ₃ -H, C ₄ -H), 5.57 (d, J = 8 Hz, sub-formula XXVI.), 7.37 (m, aromatic H), 7.55 (s, NH), 9.00 ( s, NH), 9.15 (d, J = 8Hz, NH) and 9.31 (d, J = 8Hz, NH).

Reference Example 89

1. To a solution of (3R, 4R) -4- (methylsulfonyl) -3- (tritylamino) -2-oxoazetidine (0.407 g) in acetonitrile (10 mL) was added 0.244 g of N-acetyl cysteamine silver salt and Sodium iodide (75 g) was stirred vigorously for 5 hours. The insoluble material is filtered off and the filtrate is evaporated. The residue was dissolved in ethyl acetate and the resulting solution was washed with water and evaporated. The residue was purified by silica gel column chromatography (eluent; ethyl acetate: chloroform: methanol = 8: 8: 1). 0.297 g of 4- (2-acetylamidoethylthio) -3- (tritylamino) -2-oxoazetidine are obtained.

IR: 3250, 1750, 1670, 1615, 1485 and 1260.

2. To a solution of 0.076 g of the trityl derivative obtained in Part 1 in 20 ml of acetone was added 0.46 g of p-toluenesulfonic acid monohydrate under ice-cooling, and the resulting mixture was stirred at room temperature for 40 minutes and then concentrated. Diethyl ether was added to the residue, whereupon 3-amino-4- (2-acetamidoallylthio) -2-oxoazetidine could be isolated as a precipitate. This product is then added with stirring at -70 ° C to 0.95 g of 2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimido) acetyl chloride hydrochloride and 1.0 g of triethyl to a suspension of 20 ml of methylene chloride in methylene chloride and 2 ml of propylene oxide are added to the suspension. Subsequently, the temperature of the reaction mixture was gradually raised to room temperature over an hour. The reaction mixture was concentrated and the insoluble material was filtered off. The filtrate was purified by silica gel column chromatography (eluent: ethyl acetate: chloroform: methanol = 8: 8: 1). 0.814 g of 4- (E-2-acetamido-vinylthio) -3- [2- (2-chloro-acetamido) -2 (methoxyimino) -acetamido] -2-oxo-azetidine is obtained.

IR .nu ® * _x ^{r cm-1:} 3420, 3250, 1766, 1670, 1620, 1542, 1265 and 1045th

Reference Example 90

1. To a solution of (3S, 4S) -3-benzyloxycarbonylamido) -4-acetoxy-2-oxoazetidine (3.0 g) in acetonitrile (25 mL) was added zinc acetate (2.34 g) followed by

-271

189,545

Ethyl glycolate (3.4 g) was added and the reaction mixture stirred at 65-70 ° C for 7 hours. The solvent was distilled off and the residue was dissolved in ethyl acetate. The resulting solution was washed with water and evaporated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 1). Thus 0.372 g of (3S, 4R) 3- (benzyloxycarbonylamido) -4- (ethoxycarbonylmethoxy) -2-oxoazetidine (Compound A) and 0.604 g of the corresponding (3S, 4S) isomer (Compound B) are obtained. ) we get.

Identification of compound A:

IR: cm- ¹ : 3310, 3200, 1785, 1755, 1730, 1700, 1522 and 1260.

Identification of compound B:

IR spectrum cm3310, 1790, 1772, 1736, 1690, 1525, 1240 and 1112.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 7Hz, CH ₃ ), 4.15 (q, J = 7Hz, -CH ₂ -), 4.20 (s, -CH ₂ -), 4.31 (dd, J = 1.8Hz, C ₃ --H), 5.02 (d, J = 1Hz, C ₄ --H), 5.05 (s, --CH ₂ -), 7.36 (s, aromatic H), 7.96 (d, J = 8Hz, NH) and 8.80 (s, NH),

2. To a solution of (3S, 4S) -isomer obtained in Part 1 of Example 1 in 0.482 g of tetrahydrofuran (20 ml) is added 0.40 g of palladium on carbon and the mixture is stirred under a stream of hydrogen gas for 30 minutes. The catalyst is filtered off and the filtrate is concentrated to one third of its original volume and concentrated to 3 ml.

At the same time, a suspension of 0.574 g of 2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetyl chloride hydrochloride and 0.456 g of triethylamine in 20 ml of methylene chloride was prepared. To the suspension is added, with stirring at -70 ° C, the tetrahydrofuran solution prepared as described in the preceding paragraph, followed by addition of 2 ml of propylene oxide. The temperature of the reaction mixture was then gradually raised to room temperature over one hour. The reaction mixture was concentrated and tetrahydrofuran and a saturated aqueous sodium chloride solution were added to the residue. The tetrahydrofuran layer was separated, dried over anhydrous magnesium sulfate and the solvent was distilled off. To the residue was added diethyl ether (0.601 g) of (3S, 4S) -3- [2- (2-chloroacetamidothiazol4-yl) -2- (methoxyimino) acetamido] -4- (ethoxycarbonylmethoxy). ) -2-oxoazetidine can be isolated.

R spectrum nu * ® ^{r cm-1:} 3260, 1762, 1660 and 1,542th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.08 (t, J = 7Hz, CH ₃ ), 3.66 (q, J = 7Hz, -CH ₂ -), 3.91 (s, CH _3). ), 4.36 (s, -CH ₂ -), 4.52 (dd, J = 1.8Hz, C ₃ -H), 4.91 (d, J = 1Hz, C ₄ -H), 7, 39 (s, part XXV), 8.95 (s, NH), 9.23 (d, J = 8Hz, NH) and 12.84 (broad s, NH).

3. The appropriate (3S, 4R) isomer can be prepared as described in Part 2 of this example.

IR .nu ™ ^{r cm-1:} 3260, 1760, 1665 and 1555th

Reference Example 91

To a solution of (3S, trans) -3-methoxy-4-methylthio-3- (4-nitrobenzyloxycarboxamido) -2-oxoazetidine (0.612 g) in methanol (20 mL) was added palladium on carbon (10%, 10%, 50% moisture). ). The resulting mixture was stirred under a stream of hydrogen gas at room temperature for 50 minutes, then the catalyst was filtered off, 0.9 g of 10% fresh metal catalyst was added to the filtrate and stirring was continued under a stream of hydrogen gas for 50 minutes. The catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in methylene chloride (30 mL).

Then, a solution of 1.5 g of 2- (2-chloroacetamido-thiazol-4-yl) -2-methoxy-imino-acetic acid in 30 ml of methylene chloride and 1.7 g of pyridine was stirred and While maintaining at 30 ° C, the methylene chloride solution prepared as described in the previous paragraph is added followed by 0.5 ml of phosphorus oxychloride. After 30 minutes, the solvent was distilled off and the residue was dissolved in ethyl acetate. The resulting solution was washed with water and evaporated. The residue was purified by silica gel column chromatography (eluent: chloroform: ethyl acetate = 1: 5). Thus, 0.384 g of (3S, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2-methoxyimino) acetamido] -3-methoxy-4-methylthio-2-oxoazetidine is obtained. we get.

IR .nu ™ _x ^{r cm-1:} 3230, 1765, 1670 and 1535th

NMR (d ₆ -DMSO, ppm): 2.20 (s, _CH3), 3.63 (s, _CH3), 4.05 (s, _CH3), 4.37 (s, ₂ C1CH -), 4.88 (s, C ₄ -H) and 7.75 (s, part XXV).

Reference Example 92

(3S, 4R) -4-Azido-3- [2- (4-ethyl-2,3-dioxopiperazine carboxamido) -4-pentinamido] -2-oxoazetidine can be prepared as described in Reference Example 70.

IR spectra: cm- ¹ : 3260.2105, 1756.1705, 1665 and 1500.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 7Hz, CH ₃ ), 2.71 (m, -CH ₂ -), 2.84 (m, HC =), 3, 40 (q, J = 7Hz, _-CH2 -), 3.56 (m, - CH ₂ -), 3.92 (m, _-CH2 -), 5.10 and 5.16 (both dd, J = 4.8Hz, C ₃ - H), 5.30 and 5.32 (both d, J = 4Hz, _C4 -H), 9.06 (m, NH) and 9.41 (d, J = 8 Hz , NH).

Reference Example 93

4- (2-Acetamidoethylthio) -3- [2- (4-ethyl-2,3-dioxopiperazinecarboxamido) -2-phenylacetamido] -2-oxo may be prepared as described in Reference Example 77. azetidine in the form of a mixture of cis and trans isomers.

IR .nu ™ ^{r cm-1:} 3280, 1755, 1710, 1670, 1500, 1220, 1180, 1012th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.78 and 1.80 (both s, CH ₃ ), 4.55 (dd, J = 2.8Hz, C ₃ H),

4.64 (d, J = 2Hz, C ₄ -H), 4.86 (d, J = 5Hz, C ₄ - H), 5.28 (m, C ₃ - H), 5.46 to 5, 63 (both

-281

189,545 d, J = 8Hz, XXVI. 9.27 and 9.31 (both d, J = 8Hz, NH), 9.78 and 9.82 (both d, J = 8Hz, NH).

Reference Example 94

(3S, 4R) -4-Azido-3- [2- (2-formamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine can be prepared as described in Reference Example 70.

I R spectrum nu, ™ ^{r cm-1:} 3230.2102, 1770, 1660, 1540, 1280, 1048th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.91 (s, CH 3), 5.20-5.40 (m, C ₃ -H, C ₄ -H), 7.40 (s, XXV). ), 8.50 (s, CHO), 9.02 (s, NH) and

9.54 (d, J = 8Hz, NH).

Reference Example 95

4- (2-Acetamidoethylthio) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2 - {2-oxo-3- (thiophene-3) can be prepared as described in Reference Example 77. -aldimino) imidazolidin-l-yl / -karboxamidoj-acelamido] 2-azetidinone.

I R spectrum nu ^ ^r cm 3290, 1760, 1720, 1670, 1520, 1390, 1264 and 1220th

Nuclear Magnetic Resonance Spectrum (d ₀ -DMSO, ppm): 1.83 (s, CH 3), 4.37 (s, ClCH ₂ -), 5.49 (d, J = 8Hz, part of Formula XXVI), 7, O 2 (br s, NH), 7.83 and 7.85 (both s, XXV), 7.71 (br s, NH) and 9.0-9.3 (br m, NH).

Reference Example 96

With cooling under ice-water, 1.8 g of (3R, 4R) -3-amino-4- (2-acetamidoethylthio) -2-oxoazetidine-p-toluenesulfonate and 1.5 g of triethylamine in 10 ml of methylene chloride were added. solution

2.2 g of 2- (2-chloroacetamido-thiazol-4-yl) -2- [1-methyl-1- (2-trimethylsilyl-ethoxycarbonyl) -ethoxyimino] -acetic acid, 1.02 of the corresponding acid chloride prepared in known manner from 10 g of phosphorus pentachloride and 35 ml of methylene chloride, the mixture is stirred for 30 minutes and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: methanol = 9: 1). 0.83 g of (3R, 4R) -4- (2-acetamidoethylthio) -3- {2- (2-chloroacetamidothiazol-4-yl) -2- [1-methyl-1- ( 2-trimethylsilyl-ethoxycarbonyl) -ethoxyimino] -acetamido} -2-oxo-azetidine is obtained.

IR .nu CNC ™ ^r ': 1760, 1660, 1545, 860 and 840th

NM R Spectrum _(CDCl3, ppm): 1.00 (t, J = 8Hz, -CH, -), 1.60 (s, CH), 1.63 (s, _CH3), 1.95 ( s, COCHj), 2.76 (m, _-CH2 -), 3.60 (m, - CH ₂ -), 4.20 (t, J = 8Hz, _-CH2 -), 4.26 (s , -CH ₂ -), 5.03 (d, J = 4Hz, C ₄ -H), 5.60 (dd, J = 4.8Hz, C ₃ -H), 7.03 (bs, NH) , 7.46 (s, part XXV), 7.80 (s broad, NH) and 8.45 (d, J = 8Hz, NH).

Reference Example 97

Pyridine (3 ml) was added to (3R, 4R) -3-amino-4-methylthio-2-oxoazetidine-p-toluenesulfonate (0.915 g) and the resulting mixture was stirred at 25 ° C for 10 minutes and then evaporated to dryness under reduced pressure.

At the same time, 1.85 g of 2- (2-tritylaminothiazol-4-yl) 2- [1-methyl-1- (2-trimethylsilyl-ethoxycarbonyl) -ethoxyimino-acetic acid, 0.54 g. A mixture of N-hydroxy-5-norbornene-2,3-dicarboximide, 0.62 g of DCC and 15 ml of methylene chloride is stirred at 25 ° C for 1 hour, followed by addition of the solid amino derivative prepared as described in the preceding paragraph. and stirring was continued under reflux for 2 hours. The reaction mixture was filtered and the filtrate was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1: 1). Thus, 0.66 g of (3R, 4R) -4-methylthio-3-1,2- (2-tritylamino-azol-4-yl) -2- [1-methyl-1- (2-thromethyl) -Silylethoxy-carbonyl) -ethoxyimino] -acetamido {-2-oxo-azetidine is obtained.

IR nu, ¹ ^ cm⁻¹: 1775, 1735, 1680, 1620 and 1520th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 0.03 (s, CH ₃ ), 0.83 (t, J = 8Hz, -CH ₂ -), 1.63 (s, CH ₃ ), 1.70 ( s, CH), 2.10 (s, SCHj), 4.20 (t, J = 8Hz, _-CH2 -).

4.96 (d, J = 4Hz, C ₄ --H), 5.66 (dd, J = 4.8Hz, C ₃ --H), 6.60 (broad s, NH), 6.83 (s, XXV), 6.90 (s broad, NH), 7.30 (s, aromatic H) and 8.06 (d, J = 8Hz, NH).

Reference Example 98

3- [2- (2-Chloroacetamido-liazol-4-yl) -2- (methoxyimino) -acetamido] -4- (2-styramidoethylthio) -2- oxoazetidine in the form of a mixture of cis and trans isomers.

1 H NMR? Cm ^-1 : 3260, 1758, 1660, 1540 and 1039.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.75 (t, J = 7.5Hz, -CH, -), 3.89 and 3.90 (both s, CH 3). 4.37 (s, C ₁ H 2 -), 4.70 (dd, J = 2.8Hz, C 1 H), 4.74 (d, J = 2Hz, C ₄ H), 5.04 (d, J = 5Hz, C ₄ -H), 5.40 (dd, J = 5.8Hz, C ₃ -H), 8.00 and 8.10 (both d, J = 6Hz, NH), 8.79 and

8.81 (both broad s, NH), 7.38 and 9.46 (both d, J = 8Hz, NH).

Reference Example 99

In the manner described in Reference Example 89, (3R, 4R) -4- (Z-2-acetamido-vinylthio) -3- [2- (2-chloro-acetamidothiazol-4-yl) -2- (methoxy) imino) acetamido] -2-azetidinone.

IR .nu ™ ^{r cm-1:} 3260th 1770, 1666, 1542nd

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.98 (s, CH 3), 3.88 (s, CH 3), 4.36 (s, -CH 1 -), 5.09 (d, J = 4Hz, _C4 -H), 5.28 (d, J = 8Hz, part formula XXIX.), 5.41 (dd, J = 4.8Hz, C ₃ -H), 6.89 (dd,

-291

189,545

J = 8.10Hz, XXX. ), 7.44 (s, XXV), 8.85 (s, NH), 9.31 (d, J = 10Hz, NH) and

9.44 (d, J = 8Hz, NH).

Reference Example 100

3- [2- (2-Chloroacetamido-thiazol-4-yl) -2-methoxyimino-acetamido] -4- [2- (4-nitrobenzyloxycarbonyl) can be prepared as described in Reference Example 77. ethylthio] -2-oxoazetidine in the form of a mixture of cis and trans isomers.

IR spectra? Cm? ': 3255.2945, 1761, 1690, 1660, 1510, 1345, 1260, 1053 and 820.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.6-2.9 (m, -CH ₂ -), 3.1-3.4 (m, -CH ₂ -), 3.88 and 3, 90 (each s, _CH3), 4.37 (s, C1CH ₂ -), 4.71 (dd, J = 2.8Hz, C ₃ - H), 4.73 (d, J = 2Hz, C ₄ -H), 5.03 (d, J = 5Hz, C ₄ -H), 5.18 (s, -CH ₂ -), 5.40 (dd, J = 5.8Hz, C ₃ -H), 7.40 and 7.48 (both s, parts of Formula XXV), 7.59 and 8.21 (both d, J = 8Hz, aromatic H), 8.77 and 8.79 (both broad s, NH). .

Reference Example 101

(3R, 4R) -4- (2-Acetamidoethylthio-3- [2- (2-formamidothiazol-4-yl) -2- (1-sodium tetrazol-5-yl) is prepared as described in Reference Example 77. -methoxyimino) acetamido] -2-azetidinone.

IR .nu £ ® _x ^{r cm-1:} 1755.1660, 1545, 1290, 1010th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.85 (s, CH ₃ ), 2.86 (m, -CH ₂ -), 3.24 (m, Cl ₂ ), 4.98 (d, J = 5Hz, C ₄ -H), 5.30 (s, -CH ₂ -), 5.37 (dd, J = 5.8Hz, C ₃ -H), 7.42 (s, part XXV). )

8.32 (t, J = 6Hz, NH), 8.52 (s, CHO), 8.75 (s, NH) and 10.00 (d, J = 8Hz, NH).

0.845 g of (3S, 4R) 4-Azido-3- {2- (2-trityl-aminothiazol-4-yl) -2- [1-methyl- (2-trimethylsilyl-ethoxy) ethyl ester] was obtained in a similar manner. carbonyl) ethoxyimino] acetamido} -2-oxoazetidine.

IR: cm- ¹ : 3350, 3280, 2112, 1780, 1730, 1675 and 1520.

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 0.03 (s, CH ₃ ), 0.97 (t, J = 9Hz, -CH ₂ -), 1.95 (s, CH ₃ ), 1.97 ( s, CH ₃ ), 4.21 (t, J = 9Hz, --CH ₂ -), 5.33 (d, J = 4Hz, C ₄ --H), 5.56 (dd, J = 4.8Hz, C ₃ -H), 6.75 (s, moiety XXV), 6.83 (s, NH), 6.93 (s, NH), 7.31 (s, aromatic H) and 8.15 (s). d, J = 8Hz, NH).

Example 7

To a solution of (3S, 4S) -4-acetoxy-3- (phenoxyacetamido) -2-oxoazetidine (0.45 g) in dimethylformamide (4 mL) was added sulfuric anhydride-pyridine complex (0.515 g) and the reaction was allowed to stand for 5 days. The reaction mixture was then treated with diethyl ether (20 mL), and the resulting oil was washed with diethyl ether (10 mL) and dissolved in water. The resulting aqueous solution was treated with "Dowex 50W-Na" resin supplied by Dow Chemical Co., USA, followed by a column packed with "XAD-Π" resin supplied by Rohm and Haas, Co. USA. purification by chromatography. 0.462 g of (3S, 4S) -4-acetoxy-3- (phenoxyacetamido) -2-oxoazetidine-1-sulfonic acid sodium salt are obtained.

IR spectrum cm- ¹ : 3550.3250, 1768.1725, 1635, 1290, 1255 and 1058.

NMR (d ₆ -DMSO, ppm): 2.05 (s, _CH3), 4.54 (s, - CH ₂ -), 4.76 (dd, J = 2.9Hz, C ₃ -H ), 6.21 (d, J = 2Hz, C ₄ -H), 6.90-7.44 (m, aromatic H) and 9.04 (d, J = 9Hz, NH).

Reference Example 102

Under ice-cooling, a solution of (3S, 4R) -3-amino-4-azido-2-oxoazetidine-p-toluenesulfonate (1.8 g) in methylene chloride (5 ml), propylene oxide (20 ml) and pyridine (0.48 g) was added. 2 g of 2- (trimethylsilyl) ethoxycarbonyl chloride were added and the resulting mixture was stirred for 30 minutes and then concentrated under reduced pressure. Ethyl acetate was added to the residue and the insoluble material was filtered off. The filtrate was evaporated and purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1: 1). 1.085 g of (3S, 4R) -4-azido-3- [2- (trimethylsilyl) ethoxycarboxatnido] -2-oxoazetidine are obtained.

IR: cm- ¹ : 3300, 2100, 1780, 1750, 1700 and 1530.

/ 03. PREPARATION

0.598 g of (3S, 4R) -3-amino-4-azido-2-oxoazetidine tosylate, prepared as described in Reference Example 45, is known from Reference Example 97.

Example 2

0.586 g of (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine of a mixture of anti-isomers) in dimethylformamide (5 mL) was added sulfuric anhydride-pyridine complex (0.402 g) and the reaction mixture was allowed to stand for 7 days. The reaction mixture was then worked up as described in Example 1, 0.22 g of anti- (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino). acetamido] -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR .nu ™ ^r cm⁻¹: 3450.3280, 1780, 1750, 1663, 1280, 1245 and 1038th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.04 (s, CH ₃ ), 4.00 (s, CH ₃ ), 4.34 (s, -CH ₂ -), 4.74 (dd, J = 2.9Hz, C ₃ -H), 6.23 (d, J = 2Hz, C ₄ -H), 7.93 (s, part XXV.), 9.25 (d, J = 9Hz, NH) and 12.77 (s, NH).

During the separation and purification steps mentioned above, 0.188 g can be isolated from the corresponding color isomer.

IR .nu ™ ^{r cm-1:} 3425.3260, 1780.1750, 1670, 1280, 1240 and 1040th

-301

189,545

NMR (d _e -DMSO, ppm): 2.06 (s, _CH3), 3.87 (s, _CH3), 4.33 (s, _-CH2 -), 4.77 (dd, J = 2.9Hz, CH 1 -H), 6.10 (d, J = 2Hz, C ₄ -H),

7.34 (s, portion XXV), 9.45 (d, J = 9Hz, NH) and 12.87 (s, NH).

Example 3

0.101 g of syn- (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido, prepared as described in Example 2, are obtained. To a solution of the sodium salt of -2-oxoazetidine-1-sulfonic acid in 4 ml of water was added with ice-cooling and stirring, 28.4 mg of sodium monomethyl dithiocarbamate, and the resulting mixture was stirred at room temperature for one hour. The insoluble material is then filtered off and the filtrate is purified by chromatography on a column packed with "XAD-1I" resin. Thus, 55.4 mg of syn- (3S, 4S) -4-acetoxy-3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine-1- yielding the sulfonic acid sodium salt.

IR nu * ^"r cm⁻¹: 3420, 1785, 1770, 1735, 1665, 1620, 1282, 1245 and 1045th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.05 (s, CH 3), 3.15 (s, CH 3, 4.71 (dd, J = 2.8Hz, C ₃ H), 6.07 ( d, J = 2Hz, C ₄ -H), 6.71 (s, part XXV.), 7.13 (s, _NH2) and 9.35 (d, J = 8Hz, NH).

Example 4

0.101 g of anti- (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido], prepared as described in Example 2, To a solution of the 2-oxoazetidine-1-sulfonic acid sodium salt in 4 mL of water was added 29 mg of sodium monomethyl dithiocarbamate under ice-cooling and the resulting mixture was stirred at room temperature for 1 hour. The insoluble material is filtered off and the filtrate is purified by chromatography on a column packed with "XAD II". Thus, 48 mg of anti (3S, 4S) -4-acetoxy-3- [2- (2-aminothiazol-4-yl) -2-methoxyimino) acetamido] -2-oxoazetidine-1- yielding the sodium salt of sulfonic acid.

IR .nu ® * _x ^{r cm-1:} 3460, 3350.1780, 1750, 1730, 1665, 1610, 1280, 1240 and 1040th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.04 (s, CH ₃ ), 3.94 (s, CH ₃ ), 4.73 (dd, J = 2.9Hz, C ₃ -H),

6.23 (d, J = 2Hz, C ₄ -H), 7.02 (s, - _NH2), 7.32 (s, Part XXV.) And 9.18 (d, J = 9Hz, NH ).

Example 5

To a solution of (3R, 4R) -4- (methylsulfonyl) -3- (phenoxyacetamido) -2-oxoazetidine (0.18 g) in dimethylformamide (3 mL) was added sulfuric anhydride-pyridine complex (0.19 g), followed by let it stand for days. The reaction mixture was worked up as described in Example 1 to give 0.13 g of (3R, 4R) -4- (methylsulfonyl) -3- (phenoxyacetamido) 2-oxo-azetidine-1-sulfonic acid sodium salt.

IR spectrum ν cm 3, 3370, 1785, 1685, 1290, 1250 and 1058.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.16 (s, CH ₃ ), 4.53 (s, -CH ₂ -), 5.16 (d, J = 5Hz, C ₄ -H),

5.71 (dd, J = 5.10Hz, C ₃ -H), 6.80-7.43 (m, aromatic H) and 8.35 (d, J = 10Hz, NH).

Example 6

To a solution of (3S, 4R) -3- (benzyloxycarboxamido) -4-methoxy-2-oxoazetidine-0.2 g (0.2 g) in sulfur trioxide-pyridine complex (0.255 g) was added and the reaction mixture was allowed to stand for 4 days. forget it. Diethyl ether (30 ml) was added and the oil precipitated by the latter addition was washed with diethyl ether. The crystals thus precipitated were collected by filtration and washed with ethanol. 0.226 g of (3S, 4R) -3- (benzyloxycarboxamido) -4-methoxy-2-oxoazetidine-1-sulfonic acid pyridinium salt are obtained.

IR Spectrum? Cm ^-1 : 3180.1770, 1690, 1250, 1060.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.44 (s, CH ₃ ), 4.79 (dd, J 5.9Hz, C ₃ -H), 5.02 (s, -CH ₂ -), 5.05 (d, J = 5Hz, _C4 -H), 5.20 (br s, part XXXI. formula), 7.33 (s, aromatic H, 7.90 (d, J = 9Hz, NH) , 8.03 (t, J = 7Hz, part XXXII), 8.57 (t, J = 7Hz, part XXXIII), and 8.90 (d, J = 7Hz, part XXXIV).

Example 7

0.201 g of (3S) -4-azido-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine (syn-isomer, cis, trans- mixture) (0.16 g of sulfur trioxide-pyridine complex) was added to a solution of dimethylformamide (3 ml) and the reaction mixture was allowed to stand for 30 days. The reaction mixture was then worked up as in Example 1 to give (3S) 4-azido-3- [2- (2-chloroacetamidothiazol-4-yl) -2 (methoxyimino) acetamido] (0.023 g). 2-oxo-azetidine-1-sulfonic acid sodium salt (syn isomer, cis, trans mixture).

IR nu * ® ^r cm⁻¹: 3420, 3275 (shoulder), 2110, 1775, 1670, 1275 and 1050th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.88 (s, CH ₃ ), 4.13 (s, -CH ₂ -), 4.53 (dd, J = 2.8Hz, trans C ₃ - H), 5.19 (d, J = 2 Hz, trans C ₄ -H);

5.19 (dd, J = 4.8Hz, cis C ₃ --H), 5.42 (d, J = 4Hz, cis C ₄ --H), 7.40 (s, cis part of XXV), 7 , 43 (s, trans of formula XXV), 9.45 (d, J = 8Hz, cis NH), 9.48 (d, J = 8Hz, trans NH) and 12.70 (s, NH).

Example 8

0.233 g of (3R, 4R) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) acetamido] -4- (methylsulfonyl) -2-oxoazetidine ( a mixture of color and anti-isomer)

-311

To a solution of 189,545 ml of dimethylformamide was added 0.18 g of sulfuric anhydride-pyridine complex and the reaction mixture was allowed to stand for 22 days. After working up the reaction mixture as described in Example 1, 0.023 g of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) (methoxyimino) acetamido] -4- (methylsulfonyl) is obtained. ) -2-oxo-azetidine-1-sulfonic acid sodium salt (syn isomer) is obtained.

IR spectrum cm- ¹ : 3450-3400.1785, 1685, 1672, 1280, 1260 and 1052.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.84 (s, CH ₃ ), 4.33 (s, -CH ₂ ), 5.15 (d, J = 5Hz, C ₄ H),

5.71 (dd, J = 5.9Hz, C ₃ H), 7.53 (s, portion XXV), 9.45 (d, J = 9Hz, NH) and 12.88 (s, NH). ).

Further purification by column chromatography gave 0.023 g of the anti-isomer.

IR spectrum cm- ¹ : 3450-3400, 1785, 1675, 1285, 1260 and 1052.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.98 (s, CH ₃ ), 4.33 (s, -CH ₂ -), 5.20 (d, J = 6Hz, C ₄ -H), 5.78 (dd, J = 6.10Hz, C ₃ -H), 7.83 (s, portion XXV), 8.35 (d, J = 10Hz, NH) and 12.77 (s, NH ).

Example 9

To a solution of (3R, 4S) -4-ethylthio-3- (phenoxyacetamido) -2-oxoazetidine (0.201 g) in dimethylformamide (3 ml) was added sulfur trioxide-pyridine complex (0.226 g) and the reaction was allowed to stand for 5 days. The reaction mixture was worked up as described in Example 1 to give 0.084 g of (3R, 4S) -4-ethylthio-3- (phenoxyacetamido) -2-oxoazetidine-1-sulfonic acid sodium salt.

IR spectrum ν cm ^-1 : 3425, 1765, 1670, 1240 and 1050.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.18 (t, J = 7Hz, CH ₃ ), 2.62-2.90 (m, -CH ₂ -), 4.55 (s, -CH ₂ -), 4.70 (dd, J = 3.9Hz, C ₃ -H), 4.94 (d, J = 3 Hz, C ₄ -H), 6.88-7.44 (m, aromatic H ) and 9.04 (d, J = 9Hz, NH).

lO.példa

To a solution of (3R, 4R) -4-ethylthio-3- (phenoxyacetamido) 2-oxoazetidine (0.128 g) in dimethylformamide (3 mL) was added sulfur trioxide-pyridine complex (0.145 g) and the reaction mixture was allowed to stand for 4 days. Diethyl ether (30 ml) was added and the resulting oil was washed with diethyl ether to give crystals. To a solution of the pyridine salt thus obtained in 20 ml of water was added Dowex 50W-Na, and the resulting mixture was stirred for 30 minutes. The resin was then filtered off and the filtrate was lyophilized. 0.135 g of (3R, 4R) -4-atylthio-3- (phenoxyacetamido) -2-oxoazetidine-1-sulfonic acid sodium salt are obtained.

IR nu ^ / JCM ^1: 3400, 3325, 1760, 1665, 1240 and 1058th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.16 (t, J = 7Hz, CH ₃ ), 2.73 (q, J = 7Hz, -CH ₂ -), 4.57 (s, -CH ₂ -), 5.12-5.38 (m, C _{3 -} H, C _{4 -} H),

6.88-7.46 (m, aromatic H) and 8.83 (d, J = 9Hz, NH). 30

Example 11

To a solution of (3R, 4R) -4- (methylsulfinyl) -3- (phenoxyacetamido) -2-oxoazetidine (0.30 g) in dimethylformamide (4 mL) was added sulfur trioxide-pyridine complex (0.338 g) and the reaction mixture was stirred at room temperature for 3 hours. let it stand for days. The reaction mixture was worked up as in Example 1 to give 6 mg of (3S, 4R) -4- (ethylsulfinyl) -3- (phenoxyacetamido) -2-oxoazetidine-1-sulfonic acid sodium salt.

IR Spectrum ¹ : 3500-3400, 1780, 1765, 1520, 1300-1200, 1055 and 1020.

Example 12

To a solution of 0.220 g of syn (3S, 4S) -4-acetoxy-3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine in 4 ml of dimethylformamide 0.430 g of sulfur trioxide-pyridine complex was added and the reaction was allowed to stand for 10 days. The reaction mixture was worked up as described in Example 1 using (3S, 4S) -4-acetoxy-3- [2- (2-sulfonatoaminothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxo. 0.089 g of the syn isomer of the azetidine-1-sulfonic acid disodium salt and 36.2 mg of the anti-isomer thereof are obtained.

Identification of the color isomer:

IR nu * ® ^r _x cm⁻¹: 3450, 3230, 1782, 1665, 1512, 1232, 1045th

NMR (d _e -DMSO, ppm): 2.08 (s, _CH3), 3.87 (s, _CH3), 4.75 (dd, J = 2.8Hz, C ₃ -H), 6.09 (d, J = 2Hz, C ₄ -H), 6.97 (s, part XXVII.), 9.46 (d, J = 8Hz, NH) and 10.00 (br s, NH) .

Identification of the anti-isomer:

IR spectrum cm- ¹ : 3450, 3260, 1778, 1660, 1512, 1228, 1040.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.05 (s, CH),

3.99 (s, CH ₃ ), 4.73 (dd, J = 2.8Hz, C ₃ -H), 6.23 (d, J = 2Hz, C ₄ -H), 7.58 (s, XXV), 9.40 (d, J = 8Hz, NH) and 9.70 (broad s, NH).

Further purification by column chromatography gave 34.1 mg of syn- (3S, 4S) -4-acetoxy-3- [2- (2-sulfonato-amino-thiazol-4-yl) -2- (methoxy-yno) -acetamido] -2 the oxo-azetidine sodium salt is obtained.

IR nu ^ ^{B 1} JCM 3400, 3250, 1775, 1660, 1522, 1230 and 1040?

NMR (d -DMSO _o, ppm): 2.09 (s, _CH3), 3.88 (s, _CH3), 4.70 (dd, J = 2.8Hz, C ₃ -H), 5.80 (d, J = 2Hz, C ₄ H), 6.97 (s, part of XXV), 9.17 (s, NH), 9.28 (d, J = 8Hz, NH) and 9.96 (br s, NH).

Example 13

0.432 g of (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (isopropoxyimino) -acetamido] -2-oxo-azetidine in 4 mL of dimethylformamide (0.318 g) of sulfur trioxide-pyridine complex was added and the reaction was allowed to stand for 10 days. The reaction mixture was worked up as described in Example 1 (0.306 g) of (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (isopropoxy-321).

189,545 imino) -acetamido] -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR nu ^{^!} ; cm ': 3420.3270, 1780, 1760, 1668, 1540, 1280-1230, 1042.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.22 (d, J = 6Hz, CH 3), 2.06 (s, CH 3, 4.10-4.50 (m, part XXVI), 4 36 (s, _-CH2 -), 4.77 (dd, J = 2.8Hz, C ₃ - H), 6.13 (d, J = 2Hz, C ₄ - H), 7.34 (1 H , s, XXV), 9.33 (d, J = 8Hz, NH) and 12.80 (broad s, NH).

Example 14

0.250 g of (3S, 4S) -4-acetoxy-3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (isopropoxyimino) -acetamido] -2-oxo-azetidine-1-sulfonic acid To a solution of the sodium salt in 4 ml of water was added 73 mg of sodium monomethyl dithiocarbamate under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. The insoluble material is filtered off and the filtrate is purified by column chromatography on XAD-II resin to give 0.153 g of (3S, 4S) -4-acetoxy-3- [2- (2-aminothiazol-4-yl) - 2- (Isopropoxyimino) acetamido] -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR spectrum cm- ¹ : 3420-3325, 1785, 1665, 1615, 1515, 1280, 1240, 1068 and 1040.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.20 (d, J = 6Hz, CH 3), 2.06 (s, CH 3, 4.28 (heptet, J = 6Hz, Part XXVI), 4 73 (dd, J = 2.8Hz, C ₃ -H),

6.12 (d, J = 2Hz, C ₄ -H), 6.67 (s, XXV. Of the above formula), 7.14 (s, IHL and 9.21 (d, J = 8Hz, NH).

Example 15

0.50 g of (3S, 4S) -4-acetoxy-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -2-oxoazetidine in 1 mL of dimethyl 0.32 g of sulfur trioxide-pyridine complex was added to the solution of formamide and the reaction mixture was allowed to stand for 6 days. The reaction mixture was worked up as described in Example 1 (0.19 g of (3S, 4S) -4-acetoxy-3- [D2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamide). The sodium salt of -2-oxo-azetidine-1-sulfonic acid is obtained.

IR nu f ^ ^r _x cm⁻¹: 1780, 1705, 1670, 1510, 1280, 1240, 1180, 1060 and 1040th

Nuclear Magnetic Resonance Spectrum (D ₂ O (external standard), ppm):

1.20 (t, J = 7Hz, CH 2), 2.20 (s, CH 2, 3.50 (q, J = 7Hz, -CH ₂ -), 3.68 (m, -CH ₂ -), 3, 98 (m, - CH -), 4.80 (d, J = 2Hz, _C3 -H), 5.50 (s, part formula XXVI.), 6.30 (d, J = 2Hz, C ₄ —H) and

7.50 (s, aromatic H).

Juk. After working up the reaction mixture as in Example 1, 0.065 g of (3R, 4S) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4-methylthio The sodium salt of -2-oxoazetidine-1-sulfonic acid is obtained.

IR .nu ™ ^r _x ^cm-1: 1760, 1700, 1665, 1505, 1240, 1045th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 6Hz, CH 2), 2.02 (s, SCH 3, 3.62 (m, -CH ₂ -),

3.90 (m, -CH 3 -), 4.80 (dd, J = 2.8Hz, C ₃ -H),

5.42 (d, J = 6Hz, XXVI. Of the above formula), 5.80 (d, J = 2Hz, C ₄ -H), 7.40 (s, aromatic H), 9.18 (d, J = 8Hz, NH) and 9.70 (d, J = 6Hz, NH).

Example 17

0.44 g of (3S, 4S) -4-azido-3- [D-2- (4-ethyl-2,3-dioxolepiperazinecarboxamido) -2-phenylacetamido] -2-oxoazetidine 1.5 0.4 g of sulfur trioxide-pyridine complex was added to a solution of dimethylformamide (ml) and the resulting mixture was allowed to stand for 5 days. The reaction mixture was worked up as described in Example 1 (0.060 g of (3S, 4R) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenyl). Acetamido] -2-oxo-azetidine-1-sulfonic acid sodium salt is obtained.

IR spectrum cm- ¹ : 2110, 1780, 1710, 1680, 1515, 1260 and 1050.

NMR (d _e -DMSO, ppm). 1.10 (t, J = 6Hz, CH 3, 3.56 (m, -CH ₂ -), 3.90 (m, -CH ₂ -), 4.44 (dd, J = 2.8Hz, C ₃ - H), 5.10 (d, J = 2Hz, C ₄ -H), 5.44 (d, J = 6Hz, XXVI. of the above formula), 7.38 (s, aromatic H), 9.28 (d , J = 8Hz, NH) and

9.76 (d, J = 6Hz, NH).

Example 18

To a solution of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine (0.50 g) in dimethylformamide (3 ml) was added 0.55 g of sulfur trioxide dimethylformamide at -70 ° C. 3.75 ml of dimethylformamide and the reaction mixture was allowed to stand under ice-cooling for 10 hours. 0.285 g of pyridine is then added and the reaction is worked up as in Example 1. 0.481 g of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine-1-sulfonic acid sodium salt are obtained.

IR .nu ™ ^r cm⁻¹: 3380, 1782, 1760, 1710, 1512, 1255, 1070 and 1045th

NMR (d _e -DMSO, ppm): 2.05 (s, CHJ, 4.45 (dd, J = 9Hz, _C3 -H), 5.07 (s, _-CH2 -); 6.13 (d, J = 1Hz, C ₄ H), 7.40 (s, aromatic H) and 8.21 (d, J = 9Hz, NH).

Example 76

0.415 g of (3R, 4S) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4-methylthio-2-oxoazetidine 1.5 To a solution of dimethylformamide (ml) was added sulfur trioxide-pyridine complex (0.32 g) and the reaction mixture was allowed to stand for 6 days 79. example

To a solution of 0.214 g of (3S, 4S) -4-acetoxy-1- (tert-butyldimethylsilyl) -3- (phenylacetamido) -2-oxoazetidine in 3 mL of dimethylformamide is added 0.175 g at -70 ° C. of sulfur trioxide-dimethylformamide complex in 1.19 ml of dimethylformamide

-331. 189,545 and then allowed to stand at -5 ° C to + 5 ° C for 2 days. After addition of 0.091 g of pyridine, the reaction mixture was worked up as described in Example 1. 0.163 g of (3S, 4S) -4-acetoxy-3- (phenylacetamido) -2-oxoazetidine-1-sulfonic acid sodium salt are obtained.

IR nu ^ ^{r cm-1:} 3450 to 3370, 1785.1760, 1662, 1528, 1280, 1240, 1068 and 1043rd

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.03 (s, CH ₃ ), 3.46 (s, -CH ₂ -), 4.63 (dd, J = 2.9Hz, C ₃ -H ), 6.10 (d, J = 2Hz, C ₄ -H), 7.30 (s, aromatic H), and 8.96 (d, J = 9Hz, NH).

Example 20

To a solution of 0.156 g of (3S, 4S) -4-acetoxy-1- (tert-butyldimethylsilyl) -3- (2-bromo-2-phenylacetamido) -2-oxoazetidine in 2 mL of dimethylformamide A solution of sulfur trioxide-dimethylformamide (0.105 g) in dimethylformamide (0.71 ml) was added at 0 ° C and the reaction mixture was allowed to stand at -5 ° C to + 5 ° C for two days. After addition of 0.055 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.06 g of (3S, 4S) -4-acetoxy-3- (2-bromo-2-phenylacetamido) -2-oxoazetidine-1-sulfonic acid sodium.

IR nu * ^ cm ^-1: 3425, 3275, 1785, 1672, 1520, 1280, 1235, 1070 and 1,042th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.03 (s, CH ₃ ), 4.65, 4.68 (both dd, J = 1.8 Hz, C ₃ H), 5.60 (s part XXVI. formula), 6.08, 6.13 (both d, J = 1 Hz, C ₄ -H), 7.26-7.70 (m, aromatic H), and 9.37 (d, J = 8Hz, NH).

Example 21

To a solution of (3S, 4S) -4-acetoxy-3- (benzyloxycarboxamido) -2-oxoazetidine-1-sulfonic acid sodium salt (0.1 g) in water (5 ml) was added 0.016 g acetic acid and 0.05 g palladium on carbon. the resulting reaction mixture was stirred under a stream of hydrogen gas for 40 minutes. The catalyst is filtered off and the filtrate is lyophilized. 0.06 g of (3S, 4S) -4-acetoxy-3-amino-2-oxoazetidine-1-sulfonic acid sodium monoacetate salt is obtained.

IR .nu ™ ^{r cm-1:} 3450, 3270, 1778, 1740, 1670, 1638, 1238, 1042nd

NMR (d ₆ -DMSO, ppm): 2.03 (s, _CH3), 3.81 (d, J = 1Hz, _C3-H) and 5.82 (d, J = 1Hz, C ₄ -H).

Example 22

To a solution of (3R, 4R) -4- (benzothiazol-2-yl-dithio) -3-phenoxyacetamido-2-oxoazetidine (0.70 g) in dimethylformamide (3 mL) was added sulfur trioxide pyridine complex (0.8 g), then the reaction mixture was allowed to stand for 4 days. Workup of the reaction mixture as described in Example 1 gave 0.61 g of (3R, 4R) -4- (benzothiazol-2-yl-dithio) -332 '(phenoxyacetamido) -2-oxo-azetidine-1-sulfonic acid sodium salt. .

IR spectrum New cm ^-1 : 1768, 1670, 1520, 1280,

1240 and 1052.

Example 23

0.446 g of (3S, 4S) -4-acetoxy-3- [2- (benzothiophen-3-yl) 2- (2-oxo-imidazolidin-1-ylcarboxamido) -acetamido] -2-oxo-azetidine in 3 mL To a solution of dimethylformamide at -70 ° C was added 0.306 g of sulfur trioxide dimethylformamide complex in 2.09 ml of dimethylformamide, and the reaction mixture was allowed to stand at 0 ° C for 2 days. After addition of 0.159 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.141 g of (3S, 4S) -4-acetoxy-3- [2- (benzothiophen-3-yl) -2- (2-oxo-3-sulfonatoimidazolidine) was added. -1-yl-carboxamido) -acetamido] 2-oxo-azetidine-1-sulfonic acid disodium salt was obtained.

IR .nu ™ ^r cm '': 3275,1775,1710, 1660, 1525, 1270-1220 and the 1041st

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm) 2.04 (s, CH ₃ ), 3.62 (m, -CH ₂ -), 4.66-4.70 (both dd, J = 2.8Hz) , C ₃ -H), 5.84, 5.86 (both d, J = 8Hz, portion of Formula XXVI), 6.03.6.15 (both d, J = 2Hz, C ₄ -H), 7 , 30-8.10 (m, aromatic H), 8.82,

8.91 (both d, J = 8Hz, NH) and 9.27, 9.30 (both d, J = 8Hz, NH).

Further, 0.162 g of (3S; 4S) -4-acetoxy-3- [2- (benzothiophen-3-yl) -2- (2-oxo-imidazolidin-1-ylcarboxamido) -acetamido] -2-oxo-azetidine The sodium salt of -l-sulfonic acid can also be isolated.

IR .nu ® ^ _x ^{r cm-1:} 3450, 3310,1780,1710, 1668, 1520, 1250, 1045th

Example 24

0.3 g of (3 S) -4-azido-3- [2- (benzothiophen-3-yl) -2- (2-oxo-imidazolidin-1-ylcarboxamido) -acetamido] -2-oxo-azetidine in 3 mL of dimethylformamide A solution of 0.322 g of sulfur trioxide-dimethylformamide complex in 2.19 ml of dimethylformamide was added at -70 ° C and the reaction mixture was allowed to stand at 0 ° C for 3 days. After addition of 0.167 g of pyridine, the reaction mixture was worked up as described in Example 1 to give 0.0732 g of (3S) 4-azido-3- [2- (benzothiophen-3-yl) -2- (2-oxo-3-sulfonate). -imidazolidin-1-yl-carboxamido) -acetamido] 2-oxo-azetidine-1-sulfonic acid disodium salt.

IR nu f ^ _x cm ^"1: 3500 to 3400, 3300.2103, 1772, 1705, 1658, 1520, 1260-1225, 1050th

Furthermore, 0.056 g of (3S) -4-azido-3- [2- (benzothiophen-3-yl) -2- (2-oxoimidazolidin-1-ylcarboxamido) acetamido] -2-oxoazetidine-1-sulfonic acid the sodium salt may also be isolated.

IR .nu ™ ^r cm '': 3275,2102,1770,1710, 1660, 1520, 1255, 1048th

Example 25

0.349 g of (3S) -4-azido-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (isopropoxyimino) acetamido] -2-341.189,545

J = 4-9Hz, _C3 -H), 6.34 (d, J = 4Hz, _C4 -H), 6.58 (s, Part XXV.), 7.15 (s, NH), 7 , 25 (s, aromatic H) and 9.32 (d, J = 9Hz, NH).

To a solution of oxo-azetidine in 3 ml of dimethylformamide was added at-70 ° C a solution of 0.322 g of sulfur trioxide-dimethylformamide complex in 2.2 ml of dimethylformamide, and the reaction mixture was allowed to stand at 0 ° C for 2 days. . After addition of 0.17 g of pyridine, the reaction mixture was worked up as described in Example 1, using 0.254 g of (3 S) -4-azido-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (isopropoxyimino). ) -acetamido] -2-oxo-azetidine-1-sulfonic acid, sodium salt.

IR spectra: cm-1: 3490-3380, 3275, 2120, 1778, 1670, 1542, 1275 and 1050.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): δ, 25 (d, J = 6Hz, CH 3, 4.16 (trans) and 4.36 (cis (both s, -CH ₂ -), 4.30- 4.50 (m, part of Formula XXVI),

4.61 (dd, J = 2.8Hz, trans C ₃ -H), 5.21 (d, J = 2Hz, trans C ₄ -H), 5.23 (dd, J = 4-8Hz, cis C) ₃ H), 5.48 (d, J = 4 Hz, trans C ₄ -H), 7.41 (cis) and 7.44 (trans) (both s, part XXV.)

9.34 (trans) and 9.38 (cis) (both d, J = 8Hz, NH), 12.72 (cis) and 1286 (trans) (both s, NH).

Example 26

0.22 g of (3S, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (phenylacetoxy) 2-oxoazetidine To a solution of 2 ml of dimethylformamide at -70 ° C was added a solution of 0.24 g of sulfur trioxide-dimethylformamide complex in 0.96 ml of dimethylformamide and the resulting mixture was allowed to stand at 0 ° C for 17 days. After addition of 0.109 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.186 g of (3S, 4R) -3- [2- (2-chloroacetamidothiazol4-yl) -2- (methoxyimino) acetamido]. Yielding the sodium salt of 4- (phenylacetoxy) -2-oxoazetidine-1-sulfonic acid.

IR nu ^, ^r ® _K ^cm-1: 3400,3275,1780,1750, 1670, 1540, 1278, 1250 and 1,042th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.67 (ABq, J = 5-9Hz, -CH ₂ -), 3.87 (s, CH 3, 4.36 (s, -CH ₂ -), 5.42 (dd, J = 4.9Hz, C ₃ -H), 6.37 (d, J = 4Hz, C ₄ -H), 7.25 (s, aromatic H), 7.30 (s, XXV), 9.42 (d, J = 9Hz, NH) and 12.86 (s, NH).

Example 27

0.1 g of (3S, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) 2- (methoxyimino) acetamido] -4- (phenylacetoxy) -2-oxoazetidine To a solution of the sodium salt of -1-sulfonic acid in 7 ml of water was added 0.027 g of sodium monomethyl dithiocarbamate under ice-cooling, and the resulting mixture was stirred at room temperature for 1.5 hours. The insoluble material is filtered off and the filtrate is purified by chromatography on a column packed with XAD-II resin to give 0.044 g of (3S, 4R) -3- [2- (2-aminothiazol-4-yl) -2- (methoxy) imino) -acetamido] -4- (phenylacetoxy) -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR .nu £ ® ^r cm⁻¹: 3420, 3320, 1790, 1740, 1663, 1522, 1275, 1248 and 1048th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.87 (ABq, J = 11, 14Hz, -CH ₂ -), 3.92 (s, CH 3, 5.38 (dd,

Example 28

To a solution of (3R, 4R) -4-acetylthio-3- (phenoxyacetamido) -2-oxoazetidine (0.294 g) in dimethylformamide (3 mL) was added 0.459 g of sulfur trioxide-dimethylformamide complex at -70 ° C. 12 ml of dimethylformamide and the reaction mixture was allowed to stand at 0 ° C for 2 days. Then 0.24 g of pyridine is added to the reaction mixture, followed by 20 ml of diethyl ether, and the precipitated oily substance is washed twice with diethyl ether and then ethanol is added. The thus precipitated crystals of the pyridinium salt were collected by filtration, then suspended in water and treated with Dowex 50W-Na ⁺ resin. The resin is then filtered off and the filtrate is lyophilized. 0.326 g of (3R, 4R) -4-acetylthio-3- (phenoxyacetamido) -2-oxoazetidine-1-sulfonic acid sodium salt are obtained.

IR spectrum cm- ¹ : 3390, 1770, 1690, 1522, 1240 and 1052.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.27 (s, CH 3, 4.54 (s, -CH ₂ -), 5.28 (dd, J = 5.9Hz, C-H), δ , 70 (d, J = 5Hz, C ₄ H), 6.85-7.47 (m, aromatic H), 8.90 (d, J = 9Hz, NH).

Example 29

0.267 g of (3R, 4R) -4-acetylthio-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -2-oxoazetidine in 3 ml of dimethyl Formaldehyde (0.26 g) in DMF (0.26 g) and dimethylformamide (1.26 ml) were added and the reaction mixture was allowed to stand at 0 ° C for 2 days. After adding 0.138 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.302 g of (3R, 4R) -4-acetylthio-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) - 2-Phenylacetamido] -2-oxoazetidine-1-sulfonic acid sodium salt was obtained.

IR: cm- ¹ : 3390, 3280, 1768, 1708, 1670, 1505, 1275, 1250, 1182 and 1045.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.09 (t, J = 7Hz, CH 3), 1.96 (s, CH 3, 3.25-3.70 (m, -CH ₂ -), 3, 38 (q, J = 7Hz, _-CH2 -), 3.82 to 4.00 (m, - CH ₂ -), 5.33 (dd, J = 5.8Hz, C ₃ - H), 5, 43 (d, J = 7 Hz, sub-formula XXVI.), 5.49 (d, J = 5Hz, C ₄ - H), 7.38 (s, aromatic H), 9.20 (d, J = 8Hz, NH ) and 9.78 (d, J = 7Hz, NH).

Example 30

0.3 g of (3R, 4S) -4-acetylthio-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -2-oxoazetidine A solution of 0.248 g of sulfur trioxide-dimethylformamide complex in 1.69 ml of dimethylformamide was added at -70 ° C to a solution of DMF (ml) and the reaction mixture was allowed to stand at 0 ° C for 2 days. 0.129 g

-351

After addition of 189,545 pyridine, the reaction mixture was worked up as described in Example 1, 0.305 g of (3R, 4S) -4-acetylthio-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide). ) -2-Phenylacetamido] -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR spectrum n2 cm2 3460, 3280, 1772, 1708,

1675, 1508, 1278, 1255, 1180 and 1048. NMR (d6 -DMSO, ppm): 1.09 (t,

J = 7Hz, CH 3), 2.31 (s, CH ₃ ), 3.39 (q, J = 7Hz, -CH ₂ -), 3.42 -3.70 (m, -CH ₂ -), 3.80 -4.002 (m, -CH ₂ _), 4.78 (dd, J = 3.8Hz, C ₃ -H), 5.23 (d, J = 3 Hz, C ₄ -H), 5.43 (d , J = 7Hz, part XXVI), 7.38 (s, aromatic H), 9.38 (d, J = 8Hz, NH) and 9.75 (d, J = 7Hz, NH).

Example 31

0.25 g of (3R, 4R) -4-Acetylthio-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine in 3 ml of dimethyl To a solution of -formamide at -70 ° C is added a solution of 0.227 g of sulfur trioxide dimethylformamide complex in 1.56 ml of dimethylformamide and the reaction mixture is stirred at 0 ° C for 3 days. After addition of 0.12 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.208 g of (3R, 4R) -4-acetylthio-3- [2- (2-chloroacetamidothiazol-4-yl) -2 (methoxy) imino) -acetamido] -2-oxo-azetidine-1-sulfonic acid, sodium salt.

IR spectrum cm- ¹ : 3460, 3270, 1770, 1665, 1538, 1260 and 1045.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.86 (s, CH ₃ ), 3.93 (s, CH ₃ ), 4.38 (s, -CH ₂ -), 5.34 (dd, J = 5.8Hz, C ₃ -H), 5.87 (d, J = 5Hz, _C4 -H), 7.70 (s, part XXV.), 8.65 (d, J = 8 Hz, NH) and 12.94 (broad s, NH).

Example 32

0.10 g of (3R, 4R) -4-acetylthio-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine-1- 0.03 g of sodium monomethyldithiocarbamate is added to 5 ml of water of the sulfonic acid sodium salt in 5 ml of water, and the resulting mixture is stirred at room temperature for 3 hours. After working up the reaction mixture as described in Example 3, 0.016 g of (3R, 4R) -4-acetylthio-3- [2- (2-aminoacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] - The sodium salt of 2-oxoazetidine-1-sulfonic acid is obtained.

IR Spectrum ^? cm -1 3400, 1770, 1668, 1522, 1270, 1245 and 1050.

Example 33

0.30 g of (3R, 4S) -4-acetylthio-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine in 3 mL of dimethyl Formaldehyde. At 0 DEG C., a solution of sulfur trioxide dimethylformamide complex (0.273 g) in dimethylformamide (1.86 mL) was added at 70 DEG C. and the reaction mixture was allowed to stand at 0 DEG C. for 2 days. After addition of 0.142 g of pyridine 34, the reaction mixture was worked up as described in Example 1, in the amount of (3R, 4S) -4-acetylthio-3- [2- (2-chloroacetamidothiazol-4-yl) - 0.22 g]. 2- (methoxyimino) acetamido] -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR spectrum ^Br um ^Br cm -1: 3480, 3250, 1770, 1670, 1540, 1270 and 1045.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.37 (s, CH 3), 3.89 (s, CH ₃ ), 4.36 (s, -CH ₂ -), 4.95 (dd, J = 2-8Hz, _C3 -H), 5.33 (d, J = 2Hz, C ₄ - H), 7.44 (s, part XXV), 9.54 (d, J = 8 Hz, NH. ), 12.86 (br s, NH).

Example 34

0.11 g of (3R, 4S) -4-acetylthio-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine-1- To a solution of the sulfonic acid sodium salt in 5 ml of water was added 0.036 g of sodium monomethyldithiocarbamate under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. By working up the reaction mixture as in Example 3, 0.032 g of (3R, 4S) -4-acetylthio-3- (2- (2-aminothiazol-4-yl) -2-methoxyimino) acetamido] - The sodium salt of 2-oxo-azetidine-1-sulfonic acid is obtained.

IR spectrum cm- ¹ : 3410, 3315, 1768, 1665, 1515, 1270, 1245 and 1045.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.36 (s, CH ₃ ), 3.84 (s, CH ₃ ), 4.90 (dd, J = 2.8Hz, C ₃ H),

5.33 (d, J = 2Hz, C ₄ H), 6.79 (s, part of XXV), 7.16 (s, NH) and 9.42 (d, J = 8Hz, NH).

Example 35

0.25 g of (3R, 4R) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -4- (methylsulfonyl) -2- A solution of 0.202 g of sulfur trioxide-dimethylformamide complex in 1.38 ml of dimethylformamide was added to a solution of oxoazetidine in 3 ml of dimethylformamide at 70 ° C and the resulting mixture was stirred at 0 ° C for 9 days. let it stand. After addition of 0.158 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.194 g of (3R, 4R) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenyl- acetamido] -4- (methylsulfonyl) -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR nu ^ enV ^1: 3420, 3290, 1780, 1705, 1670, 1505, 1280, 1252 and 1050th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 7Hz, CH ₃ ), 2.95 (s, CH ₃ ), 3.40 (q, J = 7Hz, -CH ₂ -). ), 3.50-3.72 (m, -CH ₂ -), 3.80-4.02 (m, -CH ₂ -), 5.08 (d, J = 5Hz, C ₄ -H), 5.67 (dd, J = 5.9Hz, C ₃ -H), 5.75 (d, J = 7 Hz, sub-formula XXVI.), 7.22-7.50 (m, aromatic H), 9, 06 (d, J = 9Hz, NH) and 9.74 (d, J = 7Hz, NH).

Example 36

0.15 g of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (methylsulfo-361)

To a solution of the sodium salt of 189,545 nyl) -2-oxoazetidine-1-sulfonic acid in 5 ml of water was added 0.044 g of sodium monomethyl dithiocarbamate under ice-cooling, and the resulting mixture was stirred at room temperature for 70 minutes. After working up the reaction mixture as described in Example 3, 0.078 g of (3R, 4R) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (methyl -sulfonyl) -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR .nu ™ ^r cm '': 3400, 3325, 1782, 1670,

1612, 1520, 1278, 1250, 1050.

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 3.16 (s,

_CH3), 3.82 (s, _CH3), 5.16 (d, J = 5Hz, C ₄ - H), 5.70 (dd, J = 5.8Hz, C ₃ -H), 6, 98 (s, XXV), 7.13 (s broad, NH ₂ ) and 9.34 (d, J = 8Hz, NH).

Example 37

0.341 g of (3R, 4S) -4-methylthio-3- [2- (2-methylthioacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine with 2 mL of dimethylformamide - A solution of 0.4 g of sulfur trioxide-dimethylformamide complex in 2.7 ml of dimethylformamide is added at 70 DEG C. and the reaction mixture is allowed to stand at 0 DEG C. for 2 days. After addition of 0.206 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.246 g of (3R, 4S) -4-methylthio-3- [2- (2-methylthioacetamidothiazol-4-yl) -2- (methoxyimino). ) -acetamido] -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR .nu ™ ^{r cm-1:} 3425.3250, 1765, 1658, 1540, 1280 to 1245 and the 1045th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.17 (s, CH ₃ ), 2.22 (s, CH ₃ ), 3.38 (s, -CH ₂ -), 3.90 (s, OCH ₃ ), 4.62 (d, J = 3Hz, C ₄ H), 4.87 (d, J = 3Hz, C ₃ H) and 7.38 (s, part XXV).

Example 38

0.3 g of (3S, 4S) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-piperazinecarboxamido) -2-thienylacetamido] -2-oxoazetidine in 2 mL of dimethyl To a solution of -formamide at -70 ° C was added a solution of sulfur trioxide-dimethylformamide complex (0.307 g) in dimethylformamide (1.18 ml), and the reaction mixture was allowed to stand at 0 ° C for 2 days. After addition of 0.164 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.272 g of (3S, 4R) -4-azido-2- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide)). ) -2-thienylacetamido] -2-oxoazetidine-1-sulfonic acid sodium salt.

IR nu ^R ® ^{r cm-1:} 3480, 3280, 2105, 1772, 1708, 1670, 1505, 1275, 1242, 1185 and 1045th

NMR (d _e -DMSO, ppm): 1.09 (t, J = 7Hz, _CH3), 3.40 (q, J = 7Hz, _-CH2 -), 3.52-3.68 ( m, -CH ₂ -), 3.86-4.04 (m, -CH ₂ -),

4.47 (dd, J = 2.8Hz, C ₃ -H), 5.12 (d, J = 2Hz, C ₄ -H), 5.72 (d, J = 8 Hz, sub-formula XXVI.) 6.96-7.54 (m, aromatic H), 9.35 (d, J = 8Hz, NH) and

9.70 (d, J = 8Hz, NH).

Example 39

0.25 g of (3S, 4R) -4-azido-3- [D-2- (4-yl-2,3-dioxolepiperazinecarboxamido) -2-thienylacetamido] -2-oxoazetidine in 2 mL of dimethyl of a solution of 0.263 g of sulfur trioxide-dimethylformamide complex in 0.99 ml of dimethylformamide was added and the reaction mixture was allowed to stand at 0 ° C for 3 days. After addition of 0.137 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.224 g of (3S, 4S) -4-azido3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) - 2-thienylacetamido] -2-oxoazetidine sulfonic acid sodium salt.

IR nu ^ ^{r cm-1:} 3480, 3275.2115, 1775, 1710, 1670, 1502, 1280-1245, 1185 and 1048th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 1.09 (t, J = 7Hz, CH ₃ ), 3.42 (q, J = 7Hz, -CH ₂ -), 3.50-3.70 ( m, -CH ₂ -), 3.86-4.04 (m, -CH ₂ -),

5.15 (dd, J = 5.8Hz, C ₃ -H), 5.44 (d, J = 5Hz, C ₄ -H), 5.85 (d, J = 8Hz, portion of Formula XXVI),

6.94-7.50 (m, aromatic H), 9.33 (d, J = 8Hz, NH) and

9.74 (d, J = 8Hz, NH).

40.példa

0.40 g of (3R, 4S) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4-methylthio-2-oxoazetidine with 2 ml of dimethylformamide A solution of 0.468 g of sulfur trioxide dimethylformamide complex in 1.75 ml of dimethylformamide was added at -70 ° C and the reaction mixture was allowed to stand at 0 ° C for 2 days. After addition of 0.243 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.206 g of (3R, 4S) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyimino) -acetamide ] -4-methylthio-2-oxoazetidine-1-sulfonic acid sodium salt.

IR nu ^{R "r cm-1:} 3450, 3250, 1765, 1668, 1540, 1260 and 1042. '

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.22 (s, CH ₃ ), 3.90 (s, OCH ₃ ), 4.34 (s, -CH, -), 4.71 (dd, J = 2.8Hz, C ₃ -H), 4.79 (d, J = 2Hz, C ₄ -H), 7.40 (s, part XXV.), 9.48 (d, J = 8 Hz, NH) and

12.88 (s, NH).

Example 41 '

0.15 g of (3R, 4S) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2-methoxyimino) -acetamido] -4-methylthio, prepared as described in the previous example. To a solution of the 2-oxoazetidine-1-sulfonic acid sodium salt in 4 mL of water was added 0.044 g of sodium monomethyldithiocarbamate under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After working up the reaction mixture as described in Example 3, 0.057 g of (3R, 4S) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4-methylthio-2- yields the sodium salt of oxo-azetidine-sulfonic acid.

IR .nu ™ ^{r cm-1:} 3410, 3320, 1765, 1665, 1528, 1250 and 1050. '

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.20 (s, 35)

-371 .189,545

CH ₃ ), 3.85 (s, CH ₃ ), 4.68 (dd, J = 2.8 Hz, C ₃ H),

4.74 (d, J = 2Hz, C ₄ -H), 6.70 (s, Part XXV. Formula), 7.18 (br s, NH ₂₎ and 9.36 (d, J = 8Hz, NH ).

Example 42

0.25 g of (3R, 4S) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido] -4-methylthio-2-oxoazetidine 2 A solution of 0.26 g of sulfur trioxide-dimethylformamide complex in 0.98 ml of dimethylformamide was added at -70 ° C to a solution of dimethylformamide (ml) and the reaction mixture was allowed to stand at 0 ° C for 3 days. After addition of 0.136 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.157 g of (3R, 4S) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienyl] acetamido) -4-methylthio-2-oxoazetidine-1-sulfonic acid sodium salt.

IR spectrum New cm- ¹ : 3275, 1765, 1705, 1670, 1502, 1275, 1238, 1188 and 1045.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 7Hz, CH 3), 2.15 (s, CH 3, 3.40 (q, J = 7Hz, -CH ₂ -), 3, 48 to 3.70 (m, _-CH2 -), 3.82 to 4.04 (m, _-CH2 -), 4.54 to 4.73 (m, C ₃ -H, C ₄ -H) , 5.71 (d, J = 7Hz, portion XXVI), 6.96-7.54 (m, aromatic H), 9.40 (d, J = 9Hz, NH) and 9.72 (d, J = 7Hz, NH).

Example 43

0.3 g of (3S, 4S) -4-azido-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine in 2 mL of dimethylformamide A solution of 0.355 g of sulfur trioxide dimethylformamide complex in 1.33 ml of dimethylformamide was added at -70 ° C and the reaction mixture was allowed to stand at 0 ° C for 2 days. After addition of 0.185 g of pyridine, the reaction mixture was worked up as in Example 1, 0.269 g of (3S, 4R) -4-azido-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) ) -acetamido] -2-oxoazetidine-1 sulfonic acid, sodium salt.

IR spectrum cm- ¹ : 3490, 3250, 2110, 1775, 1667, 1535, 1260 and 1048.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.91 (s, CH 3, 4.36 (s, -CH ₂ -), 4.57 (dd, J = 2.8Hz, C ₃ -H), 5.22 (d, J = 2Hz, C ₄ H), 7.46 (s, part of XXV), 9.46 (d, J = 8Hz, NH) and 12.83 (broad s, NH). .

Example 44

0.3 g of (3S, 4R) -4-Azido-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine-2 mL of dimethyl- of formamide at -70 ° C was added a solution of 0.356 g of sulfur trioxide dimethylformamide complex in 1.33 ml of dimethylformamide at 70 ° C, and the reaction mixture was allowed to stand at 0 ° C for 2 days, after adding 0.185 g of pyridine. processed as described in Example 1, 0.259 g of (3S, 4S) -4-azido-3- [2- (2-chloroacetamidothiazol-4-yl) -2-methoxyimino) acetamido] -2 oxo-azetidine-1 sulfonic acid sodium salt.

IR nu ^ ^cm-1: 3480, 3250.2120, 1780, 1675, 1542, 1280 and 1050th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.90 (s, CH 3, 4.36 (s, -CH ₂ -), 5.22 (dd, J = 4.8Hz, C ₃ -H), 5.45 (d, J = 4Hz, _C4 -H), 7.43 (s, part XXV. formula) and 9.49 (d, J = 8Hz, NH).

Example 45

To a solution of (3R, 4S) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4-phenylthio-2-oxoazetidine (0.454 g) in dimethylformamide (2 mL) At -70 ° C, a solution of 0.459 g of sulfur trioxide dimethylformamide complex in 1.72 ml of dimethylformamide was added and the reaction mixture was allowed to stand at 0 ° C for 3 days. After addition of 0.238 g of pyridine, the reaction mixture was worked up as described in Example 1 in 0.355 g of (3R, 4S) -3- [2- (2-chloroacetamido) -thiazol-4-yl) -2- (methoxyimino) - acetamido] -4-phenylthio-2-oxoazetidine-1-sulfonic acid, sodium salt.

IR spectrum cm- ¹ : 3460, 3260, 1765, 1662, 1538, 1265 and 1042.

Example 46

0.15 g of (3R, 4S) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4-phenylthio-2- (2-chloroacetamidothiazol-4-yl) prepared as described in the previous example. To a solution of the oxoazetidine-1-sulfonic acid sodium salt in 4 ml of water was added 0.039 g of sodium monomethyldithiocarbamate under ice-cooling, and the resulting mixture was stirred at room temperature for 1.5 hours. After working up the reaction mixture as described in Example 3, 0.064 g of (3R, 4S) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4-phenylthio-2- The oxo-azetidine-sulfonic acid sodium salt is obtained.

IR spectrum λmax cm- ¹ : 3425, 3320, 1768, 1660, 1610, 1522, 1270, 1245 and 1045.

Example 47

0.44 g of (3R, 4R) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido] -4-methylthio-2-oxo To a solution of azetidine in 2 ml of dimethylformamide at -70 ° C was added 0.46 g of sulfur trioxide-dimethylformamide complex in 3 ml of dimethylformamide, and the reaction mixture was allowed to stand at 0 ° C for 2 days. After addition of 0.5 ml of pyridine, the reaction mixture was worked up as described in Example 1 in 0.154 g of (3R, 4R) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide). -2-thienylacetamido] -4-methylthio-2-oxoazetidine-1-sulfonic acid sodium salt.

IR spectrum New cm ^-1 : 1760, 1705, 1670, 1500, 1240, 1145.

NMR (d ₆ -DMSO, ppm): 1.10 (t, J = 4Hz, CHJ, 1.93 (s, SCHJ, 3.55 (m, _-CH2 -), 3.90 (m, - CH ₂ -), 5.00 (d, J = 4Hz, C ₄ --H), 5.26 (dd, J = 6.4Hz, C ₃ --H), 5.90 (d, J = 4Hz, Part XXVI), 6.90-7.53 (m, aromatic H), 9.36 (d, J = 6Hz, NH) and 9.83 (d, J = 4Hz, NH).

-381 _ 189,545.

Example 48

0.47 g of (3R, 4R) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4-methylthio-2-oxoazetidine with 2 ml of dimethylformamide A solution of 0.55 g of sulfur trioxide dimethylformamide complex was added at -70 ° C and the resulting mixture was allowed to stand at 0 ° C for 2 days. After addition of 0.5 ml of pyridine, the reaction mixture was worked up as described in Example 1, 0.365 g of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) - acetamido] -4-methylthio-2-oxoazetidine-1-sulfonic acid, sodium salt.

IR nu * ^"r cm ^-1: 1765, 1670, 1540, 1260 and 1045th

NMR (d _e -DMSO, ppm). 2.30 (s, CHJ, 4.01 (s, CHJ, 4.46 (s, _-CH2 -), 5.26 (d, J = 4Hz, _C4 -H), 5.50 (d, J = 4 Hz, C ₃ -H) and 7.65 (s, XXV. part formula).

Example 49

0.25 g of (3R, 4R) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4-methylthio-2-oxoazetidine-1-sulfonic acid To a solution of the sodium salt in 8 mL of water was added 0.078 g of sodium monomethyl dithiocarbamate under ice-cooling, and the resulting mixture was stirred at room temperature for 1.5 hours. After working up the reaction mixture as described in Example 3, 0.052 g of (3R, 4R) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4-methylthio-2- yielding the sodium salt of oxoazetidine-1 sulfonic acid.

IR .nu £ ® ^{r cm-1:} 1760.1665, 1615.1525, 1260 and 1045th

NMR (d ₆ -DMSO, D ₂ O, ppm): 2.30 (s, _CH3), 3.96 (s, _-CH2 -), 5.23 (d, J = 4 Hz, _C4 - H), 5.43 (d, J = 4Hz, C ₃ H) and 7.03 (s, part XXV).

Example 50

To a solution of 0.5 g (3R, 4R) -3- [3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarboxamido] -4-methylthio-2-oxoazetidine in 2 ml dimethylformamide A solution of sulfur trioxide-dimethylformamide complex (0.643 g) in dimethylformamide (2.4 ml) was added at 70 ° C and the resulting mixture was allowed to stand at 0 ° C for 18 hours. After adding 0.5 ml of pyridine, the reaction mixture was worked up as described in Example 1, 0.270 g of (3R, 4R) -3- [3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarboxamido] - Yielding the sodium salt of 4-methylthio-2-oxoazetidine-1-sulfonic acid.

IR nu * ® ^r cm ^- ': 1760, 1660, 1595, 1500 and 1250th

NMR (d _e -DMSO, ppm): 2.16 (s, _CH3), 2.75 (s, _CH3), 5.02 (d, J = 4Hz, _C4 -H), 5, 30 (dd, J = 4.8Hz, C ₃ -H), 7.56 (s, aromatic H), and 8.74 (d, J = 8Hz, NH).

Example 51

0.558 g of (3R, 4S) -3- [2- (2-chloro-acetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4- (1-methyl-1H-tetrazol-5-yl-thio) ) To a solution of -2-oxo-azetidine in 5 ml of dimethylformamide is added a solution of 0.268 g of sulfur trioxide-dimethylformamide complex in 2 ml of dimethylformamide at 70 ° C and the reaction mixture is allowed to stand at 0 ° C for 3 days. . After addition of 0.087 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.443 g of (3R, 4S) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) - acetamido] -4- (1-methyl-1H-tetrazol-5-ylthio) -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR spectrum ηϋϋ ®ϋ cm ^-1 : 1795, 1676,1540,1285, 1043.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.87 (s, CH ₃ ), 3.93 (s, CH ₃ ), 4.37 (s, -CH ₂ -), 5.42 (dd, J = 2.8Hz, C ₃ -H), 6.30 (d, J = 2Hz, C ₄ -H), 7.42 (s, part XXV. formula) and 9.65 (d, J = 8 Hz, NH).

Example 52

0.3 g of (3R, 4S) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4- (0.3R, prepared as described in Example 51). 1-methyl-1H-tetrazol-5-ylthio) -2-oxo-azetidine-1-sulfonic acid sodium salt in a mixture of 4 ml of water and 4 ml of pH 6.56 buffer with ice-cooling 0.0689 of sodium monomethyl dithiocarbamate was added and the reaction mixture was stirred at room temperature for 2 hours. After working up the reaction mixture as described in Example 3, 0.106 g of (3R, 4S) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (1- methyl 1 H -tetrazol-5-ylthio) -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR nu ^ cm ^- ': 3320, 1786.1661, 1608, 1520, 1270 and 1045th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.83 (s, CH ₃ ), 5.34 (dd, J = 2.8Hz, C ₃ -H), 6.31 (d, J = 2Hz, C ₄ -H), 6.74 (s, part XXV.), 7.16 (br s, NH ₂₎ and 9.52 (d, J = 8Hz, NH).

Example 53

3.4 g of (3R, 4R) -3- [2- (2-chloroacetatnido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4- (1-methyl-1H-tetrazol-5-yl) To a solution of thio) -2-oxoazetidine in 3 ml of dimethylformamide is added a solution of 0.268 g of sulfur trioxide-dimethylformamide complex in 1.27 ml of dimethylformamide at 70 ° C, and the reaction mixture is stirred at 0 ° C for 7 hours. let it stand for days. After addition of 0.176 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.318 g of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) - acetamido] -4- (1-methyl-1H-tetrazol-5-ylthio) -2-oxoazetidine-1-sulfonic acid sodium salt.

IR nu "® ^r cm ^-: 1778, 1660, 1540, 1300 and 1048th

NMR (d -DMSO _o, ppm): 3.69 (s,

-391

189,545

CH ₃ ), 3.88 (s, CH ₃ ), 4.35 (s, -CH ₂ -), 5.69 (dd, J = 4.8 Hz, C ₃ -H), 6.48 (d, J = 4Hz, _C4 -H), 7.23 (s, part XXV.) and 9.58 (d, J = 8Hz, NH).

Example 54

0.26 g of (3R, 4R) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4- (1R, 4R) prepared as in the previous example. To a solution of the sodium salt of methyl 1 H -tetrazol-5-ylthio) -2-oxo-azetidine-1-sulfonic acid in 20 ml of 50% aqueous methanol is added 0.0597 g of sodium monomethyl dithiocarbamate under ice-cooling, followed by The reaction mixture was stirred at room temperature for 5 hours. After working up the reaction mixture as described in Example 3, 0.093 g of (3R, 4R) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (1- methyl 1 H -tetrazol-5-ylthio) -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR .nu £ ⁸ x ^{r cm-1:} 3420.3320, 1786, 1671, 1520, 1285, 1,053th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.68 (3H, CH ₃ ), 3.87 (3H, CH ₃ ), 5.68 (dd, J = 4.8Hz, C ₃ -H),

6.42 (s, Part XXV.), 6.46 (d, J = 4 Hz, C ₄ - H), 7.12 (br s, NH) and 9.48 (d, J = 8Hz, NH) .

Example 55

0.367 g of (3S, 4R) -4-acetoxy-2- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido] -2-oxoazetidine in 2 mL of dimethyl To a solution of -formamide at -70 [deg.] C., a solution of sulfur trioxide-dimethylformamide complex (0.147 g) in dimethylformamide (2.5 ml) was added and the reaction mixture was allowed to stand at 0 [deg.] C. for 7 days. After addition of 0.195 g of pyridine, the reaction mixture was refluxed

Work up as in Example 1, 0.162 g of (3S, 4R) -4-acetoxy-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-thienylacetamido] - Yielding 2-oxo-azetidine-1-sulfonic acid sodium salt.

IR spektrumnü ^ ^{B r} s * cm ': 3280, 1780, 1750, 1710, 1668, 1502, 1280, 1230, 1182, 1042nd

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.09 (t, J = 7Hz, CH ₃ ), 1.71 (s, CH ₃ ), 3.39 (q, J = 7Hz, -CH ₂ -). ), 5.28 (dd, J = 4.9Hz, C ₃ -H), 5.80 (d, J = 8 Hz, sub-formula XXVI.), 6.18 (d, J = 4Hz, _C4 -H ), 9.28 (d, J = 9Hz, NH) and 9.72 (d, J = 4Hz,

C ₄ -H).

Example 56

To a solution of 0.206 g of (3S, 4R) -4-acetoxy-3- (thienylacetamido) -2-oxoazetidine in 2 ml of dimethylformamide at -70 ° C is added 0.147 g of sulfur trioxide-dimethylformamide complex 2.4 ml of dimethylformamide and the reaction mixture was allowed to stand at 0 ° C for 4 days. After addition of 0.182 g of pyridine, the reaction mixture was worked up as described in Example 1 to give 0.135 g of (3S, 4R) -4-acetoxy-3- (2-thienylacetamido) -2-oxoazetidine-1-sulfonic acid sodium salt.

IR nu ^ ^r x ^{8 cm-1:} 3450, 3350,1770,1740, 1668, 1530, 1290, 1240 and 1050th

'

NMR (d ₆ -DMSO, ppm): 1.96 (s, _CH3), 3.69 (s, _-CH2 -), 5.22 (dd, J = 4.9Hz, C ₃ -H ), 6.21 (d, J = 4Hz, _C4 -H), 6.82 to 7.02 (m, aromatic H), 7.23-7.44 (m, aromatic H), and 8.88 ( d, J = 9Hz, NH).

Example 57

0.404 g of (3S, 4R) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine in 3 mL of dimethylformamide A solution of 0.147 g of sulfur trioxide dimethylformamide complex in 3.1 ml of dimethylformamide was added at -70 ° C and the resulting reaction mixture was allowed to stand at 0 ° C for 7 days. After addition of 0.237 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.373 g of (3S, 4R) -4-acetoxy-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino)). ) -acetamido] -2-oxoazetidine-1 sulfonic acid, sodium salt.

IR .nu £ ⁸ x ^'cm-1: 3270.1785, 1760, 1675, 1521, 1285, 1240, 1050th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.02 (s, CH ₃ ), 3.89 (s, CH ₃ ), 4.36 (s, -CH ₂ -), 5.37 (dd, J = 4.9Hz, C ₄ -H), 6.29 (d, J = 4Hz, _C4 -H), 7.30 (s, part XXV.), 9.37 (d, J = 9Hz, NH) and

12.8 (bs, NH).

Example 58

0.187 g of (3S, 4R) -4-acetoxy-3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -2-methanol, prepared as described in the previous example. To a solution of the oxoazetidine-1-sulfonic acid sodium salt in 6 ml of a pH 6.86 buffer is added 0.048 g of sodium monomethyl dithiocarbamate under ice-cooling, and the resulting mixture is stirred at room temperature for 2 hours. After working up the reaction mixture as described in Example 3, 0.078 g of (3R, 4R) -4-acetoxy-3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) -acetamido] -2- The oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR nu * ^r x ^{8 cm-1:} 3420, 3320, 1775, 1668, 1615, 1520, 1280, 1240 and 1,042th

Nuclear Magnetic Resonance Spectrum (D ₆ -DMSO, ppm): 2.01 (s, CH ₃ ), 3.84 (s, CH ₃ ), 5.34 (dd, J = 4.9Hz, C ₃ -H),

6.26 (d, J = 4Hz, _C4 -H), 6.58 (s, Part XXVII.), 7.15 (br s, NH) and 9.29 (d, J = 9Hz, NH) .

Example 59

0.61 g of the (3S, 4S) -4-acetoxy-3-amino-2-oxoazetidine-1-sulfonic acid sodium salt acetate salt prepared in Example 21 was prepared in 20 mL of a 1: 1 mixture of water and tetrahydrofuran. To this solution was added 0.61 g of phenylacetyl chloride under ice-cooling while maintaining the pH of the reaction mixture between 7.0 and 7.5 with sodium bicarbonate. After the addition, the reaction mixture was stirred at the same temperature for a further 1.5 hours and then the tetrahydrofuran was evaporated under reduced pressure. The residue was chromatographed on a column packed with resin 401.189 545 capsules XD-II to give 0.42 g of (2S) -4-acetoxy-3- (phenylacetamido) -2-oxoacetate. <1 µm 1-sulfonic acid sodium salt. The infrared and nuclear magnetic resonance spectroscopy data for this chemical are consistent with the corresponding data for the compound prepared as described in Example 19.

Example 60

1. 0.625 g of (3S, 4R) -4-Azido-3- {2 - [(2-tritylaminothiazol-4-yl) carboxymethyliminoxy] -2-methylpropionamido} -2-azetidinone To a solution of dimethylformamide (ml) was added a solution of sulfur trioxide (0.459 g) in dimethylformamide (1.8 ml) and the resulting mixture was allowed to stand at 0 ° C for 2 days. 0.238 g of pyridine are then added to the reaction mixture, which is then washed with diethyl ether. After evaporation, the residue is dissolved in 50% aqueous ethanol, and 0.504 g of sodium bicarbonate is added to the resulting solution under ice-cooling, and the mixture is stirred for 30 minutes. The ethanol is then distilled off and the residue is purified by chromatography on a column packed with XAD-II resin. Thus, 0.181 g of (3S, 4R) -4-azido-3- {2 - [(2-tritylaminothiazol-4-yl) carboxylato-methyliminoxy] -2-methylpropionamido} -2-oxo yielding the disodium salt of azetidine-1-sulfonic acid.

IR nu ^ x ^{_B r cm-1:} 3390.2105, 1770, 1615, 1520, 1270, 1245, 1045th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.58 (s, CH 3, 1.65 (s, CH 3, 4.46 (d, J = 2Hz, C ₃ H), 5.43 (d, J = 2Hz, C ₄ -H), 6.63 (s, part XXV.) and 7.00 -7.50 (m, aromatic H).

2. To a solution of the compound prepared in Part 1 of Example 1 in 0.156 g of 50% aqueous methanol in ice-cooling is added 0.84 ml of n-hydrochloric acid, and the resulting mixture is stirred at room temperature for 2.5 hours. Sodium bicarbonate (0.07 g) was added to the mixture under ice-cooling, and the mixture was stirred for 20 minutes and the methanol was distilled off. The insoluble material in the residue is filtered off and the filtrate is purified by chromatography on a column packed with XAD-II, 0.067 g of (3S, 4R) -3- {2 - [(2-amino-thiazol-4-yl) -carboxylato-methyliminoxyl]. ) -2-methylpropionamido} -4-azido-2-oxoazetidine-1-sulfonic acid disodium salt.

IR .nu ™ ^r cm⁻¹: 3390, 2115, 1775, 1605, 1512, 1270, 1240 and 1048th

NMR (d _e -DMSO, ppm): 1.67 (s, CHJ, 4.70 (d, J = 2Hz, _C3 -H), 5.80 (d, J = 2Hz, C ₄ -H ) and 7.09 (s, part of Formula XXV).

Example 61

1. 0.4 g of (3R, 4R) -3- {2- [1- (2-trimethylsilyl-ethoxycarbonyl) -1-methyl-ethoxyimino] -2- (2-trityl-aminothiazole-4-) To a solution of 2'-acetamido} -4-methylthio-2-oxoazetidine in 2 ml of dimethylformamide was added 0.8 g of tetra-n-butylammonium fluoride, and the resulting mixture was stirred at room temperature for 30 minutes. The dimethylformamide was then distilled off and the residue was dissolved in ethyl acetate. The resulting solution was washed with water and evaporated to give 0.4 g of (3R, 4R) 3- [2- (1-carboxy-1-methylethoxyimino) -2- (2-tritylaminothiazole-4-). yl) -acetamido] -4-methylthio-2-oxoazetidine-tetra-n-butylammonium salt. This solution was then dissolved in 2 ml of dimethylformamide and a solution of 0.511 g of sulfur trioxide-dimethylformamide complex in 2 ml of dimethylformamide was added at -70 ° C. After allowing the reaction mixture to stand at 0 ° C for 2 days, pyridine (0.5 mL) was added and worked up as described in Example 1. Thus, 0.150 g of (3R, 4R) -3- [2- (1-carboxy-1-methyl-ethoxyimino) -2- (2-trityl-aminothiazol-4-yl) -acetamido] -4-methylthio-2 is obtained. The sodium salt of -oxoazetidine-1-sulfonic acid is obtained.

IR spectrum cm- ¹ : 1760, 1660, 1610, 1525, 1250.

2. To a solution of the compound obtained in Part I of Example 1 in 0.18 g of 50% aqueous methanol (15 ml) was added 1 ml of n-hydrochloric acid solution under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. Subsequently, the reaction mixture was worked up as described in Example 60, Part 2, 0.31 g of (3R, 4R) -3- [2- (2-aminothiazol-4-yl) -2- (1-carboxylato-1- methyl ethoxyimino) acetamido] 4-methylthio-2-oxoazetidine-1-sulfonic acid disodium salt.

IR spectrum: ν ^Br cm ^-1 : 1760, 1675, 1600, 1250, 1050.

Example 62

To a solution of (3S, 4R) -4-azido-3- (D-2-ureido-2-thienylacetamido) -2-oxoazetidine (0.4 g) in dimethylformamide (3 ml) was added 0.594 g of sulfur at 20 ° C. solution of tri-oxide-dimethylformamide complex in dimethylformamide (2.2 ml) and the resulting reaction mixture was allowed to stand at 0 ° C for 2 days. Thereafter, 0.307 g of pyridine was added to the reaction mixture, which was worked up and purified as described in Example 1. Thus, on the one hand, 0.131 g of (3S, 4S) -4-azido-3- (D-2-ureido-2-thienylacetamido) -2-oxoazetidine-1-sulfonic acid sodium compound (Compound A) and 0.198 g (3S, 4S) -4-Azido-3- [D-2- (3-sulfonato-ureido) -2-thienylacetamido] -2-oxo-azetidine-1-sulfonic acid disodium salt (Compound B) is obtained.

Identification of Compound A:

IR spectrum? _x ^{r cm-1:} 3315, 2120, 1770, 1660, 1520, 1240 and 1050th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm) 5.25 (d, J = 5Hz, C ₃ -H), 5.54 (d, J = 5Hz, C ₄ -H), 5.76 (s, XXVI and 7.03-7.67 (m, aromatic H).

Identification of Compound B:

IR .nu £ ^Br cm ^-1: 3320, 2120, 1775, 1665, 1520, 1242 and 1050th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 5.26 (d, J = 5Hz, C ₃ -H), 5.56 (d, J = 5Hz, C ₄ -H), 5.76 (s, XXVI) and 7.05-7.63 (m, aromatic H).

-411

189,545

Example 63

1.0,485 g of (3R, 4S) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) acetamido] -4- (methoxycarbonylmethylthio) -2-oxo- To a solution of azetidine in 2 ml of dimethylformamide at -70 ° C was added 0.495 g of sulfur trioxide-dimethylformamide complex in 1.85 ml of dimethylformamide, and the reaction mixture was allowed to stand at 0 ° C for 2 days. After addition of 0.256 g of pyridine, the reaction mixture was worked up as described in Example 1 with 0.43 g of (3R, 4S) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino). acetamido] -4- (methoxycarbonylmethylthio) -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR spectrum cm- ¹ : 2330, 1763, 1742, 1665, 1540, 1273, 1040.

NMR (d _e -DMSO, ppm): 3.67 (s, _CH3), 3.74 (AB q, J = I6Hz, _S-CH2 -), 3.93 (s, CH₂), 4, 37 (s, C ₁ -C ₂ -), 4.74 (dd, J = 2.8Hz, C ₃ -H), 5.01 (d, J = 2Hz, C ₄ -H), 7.40 (s, XXV and 9.49 (d, J = 8Hz, NH).

2. To a solution of 0.273 g of the compound obtained in Part 1 of Example 1 in 6 ml of a pH 6.86 buffer solution was added 67.8 mg of sodium monomethyl dithiocarbamate under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. After working up the reaction mixture as described in Example 3, 0.12 g of (3R, 4S) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4- ( methoxycarbonylmethylthio) -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR nu * x ^{_B r cm-1:} 3420, 3320,1763,1722, 1661, 1610, 1520, 1275 and 1043rd

NMR (d _e -DMSO, ppm): 3.66 (s, CH), 3.72 (AB quartet, J = 16 Hz, S_CH ₂ -), 3.86 (s, _CH3), 4.67 ( dd, J = 2.8Hz, C ₃ -H), 4.98 (d, J = 2Hz, C ₄ -H), 6.70 (s, part XXV.), 7.16 (br s, NH ₂ ) and 9.36 (d, J = 8Hz, NH).

Example 64

0.74 g of 4- (E-2-acetamido-vinylthio) -3- [2- (2-chloro-acetamido) -2- (methoxyimino) -thiazol-4-yl-acetamido] -2-oxo-azetidine 4 A solution of 0.734 g of sulfur trioxide-dimethylformamide complex in 2.88 ml of dimethylformamide was added at -20 ° C to a solution of dimethylformamide (ml) and the resulting mixture was allowed to stand at 0 ° C for 2 days. After adding 0.38 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.157 g of (3R, 4R) -3- [2- (2-chloroacetamido) -2-methoxyimino) thiazol-4-yl -acetamido] -4- (E-2-acetamido-chloro) -2-oxo-azetidine-1-sulfonic acid sodium salt.

IR .nu £ f _x ^{r cm-1:} 1766.1670, 1620, 1542, 1265 and 1045th

Example 65

To a solution of (3S, cis) -3- (benzyloxycarboxamido) -4-ethoxy-3-methoxy-2-oxoazetidine (0.138 g) in dimethylformamide (1.5 mL) was added 0.23 g of sulfur trioxide at 70 ° C. dimethylformamide complex in 0.86 ml of dimethylformamide and the resulting reaction mixture was allowed to stand at 0 ° C for 4 days. After addition of 0.12 ml of pyridine, the reaction mixture was worked up as described in Example 1 to give 0.088 g of the (3S, cis) -3- (benzyloxycarboxamido) -4-ethoxy-3-methoxy-2-oxoazetidine-1-sulfonic acid sodium salt. .

IR spectrum cm- ¹ : 3390, 1775, 1715, 1490, 1250 and 1050.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.03 (t, J = 7Hz, CH ₃ ), 3.34 (s, CH ₃ ), 4.91 (s, C ₄ -H), δ, 07 (ABq, -CH * ₂ -), 7.37 (s, aromatic H) and 8.12 (s, NH).

Example 66

To a solution of (3S, trans) -3-methoxy-4-methylthio-3- (4-nitro-benzyloxycarboxamido) -2-oxo-azetidine (0.161 g) in dimethylformamide (1.5 mL) was added 0.23 g of sulfur. solution of trioxide-dimethylformamide complex in 0.86 ml of dimethylformamide and the resulting mixture was allowed to stand at 0 ° C for 4 days. After addition of 0.12 ml of pyridine, the reaction mixture was worked up as described in Example 1 to give 0.138 g of (3S, trans) -3-methoxy-4-methylthio-3- (4-nitrobenzyloxycarboxamido) -2-oxoazetidine-1. -sulfonic acid sodium salt.

IR spectrum: ν max / cm ^-1 : 1770.1720, 1515, 1350, 1280, 1250 and 1050.

NMR (d _e -DMSO, ppm): 2.17 (s, CH), 3.41 (s, CH), 4.77 (s, C ₄ -H), 5.22 (s, -CH ₂ -), 7.66 and 8.23 (both d, J = 8Hz, aromatic H) and 8.48 (s, NH).

Example 67

1.0405 g of (3R, 4R) -3- [2- (2-Chloroacetamido-thiazol-4-yl) -2- (methoxyimino) acetamido] -4- (methoxycarbonylmethylthio) -2- To a solution of oxo-azetidine in 2 ml of dimethylformamide at -70 ° C was added 0.416 g of sulfur trioxide-dimethylformamide complex in 1.55 ml of dimethylformamide, and the resulting mixture was allowed to stand at 0 ° C for 2 days. . After addition of 0.427 g of pyridine, the reaction mixture was worked up as described in Example 1 to give 0.12 g of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamide. ] -4- (methoxycarbonylmethylthio) -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR spectra cm ^-1 : 3460.3260, 1778, 1729,

1660, 1540, 1270 and 1040.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.61 and 3.84 (ABq, J = 15 Hz, -CH ₂ -), 3.64 (s, CH ₃ ), 3.88 (s, CH ₃ ). ), 4.35 (s, C ₁ -C ₂ -), 5.36 (d, J = 5Hz, C ₄ -H),

5.37 (dd, J = 5.8Hz, C ₃ H), 7.49 (s, part XXV) and 9.53 (d, J = 8Hz, NH).

2. To a suspension of 0.315 g of the compound obtained in Part 1 of Example 1 in 10 ml of 50% aqueous methanol is added 0.074 g of sodium monomethyl dithiocarbamate under ice-cooling, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is known in Example 3 from Example 421

In a work-up of 180,545, 87 mg of (3R, 4R) 3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (methoxycarbonylmethylthio) The sodium salt of -2-oxoazetidine-1-sulfonic acid is obtained.

IR spectrum cm- ¹ : 3310.1767.1728.1665, 1612, 1525, 1270 and 1048.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.60 and 3.84 (ABq, J = 15Efz, - SCH ₂ -), 3.65 (s, CH ₃ ), 3.84 (s, CH ₃ ), 5.28 (d, J = 5Hz, C ₄ -H), 5.88 (dd, J = 5.8Hz, C ₃ -H), 6.85 (s, part of Formula XXV),

7.13 (broad s, NH ₂ ) and 9.42 (d, J = 8 Hz, NH).

Example 68

1. 0.4 g of (3R, 4S) -3- [D-2- (2-oxo-imidazolidin-1-ylcarboxamido) -2-phenylacetamido] -4-phenylthio-2-oxoazetidine with 3 mL of dimethylformamide A solution of 0.28 g of sulfur trioxide dimethylformamide complex in 1.04 ml of dimethylformamide was added at -70 ° C and the resulting mixture was allowed to stand at 0 ° C for 2 days. After addition of 0.144 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.243 g of (3R, 4S) -3- [D-2- (2-oxo-imidazolidin-1-ylcarboxamido) -2-phenylacetartido]. -4-phenylthio-2-oxoazetidine-1-sulfonic acid sodium salt was obtained.

IR spectra: cm-1: 3280, 1765, 1715, 1665, 1528, 1262, 1050. ¹

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.24-3.46 (m, -CH ₂ -), 3.64-3.90 (m, -CH ₂ -), 4.54 (d, J = 2Hz, _C3 -H), 4.86 (d, J = 2Hz, C ₄ - H), 5.36 (s, sub-formula XXVI), 7.36 (s, aromatic H), and 7. 37 (s, aromatic H).

2. In addition to the compound mentioned in Example 1 Part 1, 0.119 g of (3R, 4S) -3- [D-2- (2-oxo-3-sulfonatoimidazolidin-1-ylcarboxamido) -2-phenylacetamido] -4- phenylthio-2-oxoazetidine-1-sulfonic acid disodium salt is also obtained.

IR spectrum cm-1: 3450.3305, 1765, 1715,

1668, 1525, 1255, 1050.

NMR (d _e -DMSO, ppm): 3.20 to 3.44 (m, _-CH2 -), 3.54 to 3.84 (tn, - CH ₂ -), 4.45 (dd, J = 2.9Hz, C ₃ -H), 4.83 (d, J = 2Hz, C ₄ -H), 5.36 (d, J = 8 Hz, sub-formula XXVI.), from 7.20 to 7, 60 (m, aromatic H), 7.36 (s, aromatic H), 9.02 (d, J = 8Hz, NH), 9.31 (d, J = 9Hz, NH).

Example 69

1-4 ° C 0.4 g of (3S, 4S) -4-azido-3- [D-2- (2-oxo-imidazolidin-1-yl-carboxamido) -2-phenyl-acetamide] -2- To a solution of oxo-azetidine in 4 ml of dimethylformamide was added a solution of 0.337 g of sulfur trioxide dimethylformamide complex in 1.26 ml of dimethylformamide, and the reaction mixture was allowed to stand at 0 ° C for 2 days. 0.165 g of pyridine is then added and the reaction mixture is worked up as described in Example 1, 0.186 g of (3S, 4R) -4-azido-3- [D-2- (2-oxo-imidazolidin-1-ylcarboxamido) is added. Yielding the sodium salt of -2-phenylacetamido-2-oxoazetidine-1-sulfonic acid.

IR spectrum cm- ¹ : 3290.2115, 1775, 1715, 1662, 1522, 1270 and 1050.

NMR (d _e -DMSO, ppm): 3.16 to 3.48 (m, - CH ₂ -), 3.58 to 3.86 (m, _-CH2 -), 4.44 (dd,

J = 2.8Hz, C ₃ -H), 5.09 (d, J = 2Hz, C ₄ -H), 5.39 (d, J = 7 Hz, sub-formula XXVI.), 7.36 (s, aromatic H), 7.55 (s, NH), 9.02 (d, J = 7Hz, NH) and 9.21 (d,

J = 7Hz, NH).

2. Further, 0.111 g can be isolated · (3S, 4R) -4-Azido-3- [D-2- (2-oxo-3-sulfonatoimidazolidin-1-ylcarboxamido) -2-phenylacetamido} -2- also oxo-azetidine-1-sulfonic acid disodium salt.

IR spectrum ηΰ * _δ cm ^-1 : 3460,3300,2120,1765, 1708, 1663, 1522, 1255 and 1052.

NMR (d _e -DMSO, ppm): 3.20 to 3.44 (m, _-CH2 -), 3.57 to 3.80 (m, _-CH2 -), 4.42 (dd,

J = 2.8Hz, C ₃ -H), 5.11 (d, J = 2Hz, C ₄ -H), 5.39 (d, J = 7 Hz, sub-formula XXVI.), 7.36 (s, aromatic H), 9.02 (d, J = 7Hz, NH) and 9.21 (d, J = 8Hz, NH).

Example 70

-70 ° C 0.16 g of (3S, trans) -3- [D-2- (4-cyclohexyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -3-methoxy- To a solution of 4-methylthio-2-oxoazetidine in 1.5 ml of dimethylformamide was added a solution of 0.142 g of sulfur trioxide-dimethylformamide in 0.53 ml of dimethylformamide, and the reaction mixture was stirred at 0 ° C for two days. let it stand. Pyridine (0.075 mL) was added and the reaction was worked up as described in Example 1. Thus, 0.115 g of (3S, trans) -3- [D-2- (4-cyclohexyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -3-methoxy-4-methylthio-2- yielding the sodium salt of oxo-azetidine-1-sulfonic acid.

IR: 3275, 2925, 1770, 1705, 1665, 1500, 1250 and 1050.

NMR (d _e -DMSO, ppm): 1.92 (s, _CH3), 3.26 (s, _CH3), 4.73 (s, C ₄ -H), 5.60 (d, J = 7Hz, part XXVI), 7.2-7.6 (m, aromatic H), 9.22 (s, NH) and 9.78 (d, J = 7Hz, NH).

Example 71

0.35 g of (3S, 4S) -4-azido-3- (D-2- [3-methyl-3- (methylcarbamoyl) -1-ureido] -2-phenylacetamide) at -70 ° C. To a solution of 2-oxoazetidine in 3 ml of dimethylformamide was added 0.429 g of sulfur trioxide dimethylformamide complex in 1.6 ml of dimethylformamide, and the reaction mixture was allowed to stand at 0 ° C for two days. and the reaction mixture was worked up as described in Example I, 0.22 g of (3S, 4R) -4-azido-3- {D-2- [3-methyl-3- (methylcarbamoyl) -1-ureido]. ] -2-phenylacetamido} -2-oxoazetidine-1-sulfonic acid sodium salt.

IR spectrum cm-1: 3380, 2120, 1778, 1678, 1676, 1502, 1250 and 1050.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.67 (d, J = 4Hz, CH ₃ ), 3.09 (s, CH ₃ ), 4.42 and 4.46 (both dd, J = 2). , 8Hz, _C3 -H), 5.09 and 5.13 (both d, J = 2Hz, C ₄ -H), 5.35 (d, J = 8Hz, sub-formula XXVI.), 7.36 ( s, aromatic H), 9.17 (d, J = 8Hz, NH) and 9.89 (d, J = 8Hz, NH).

-431

189,545

Example 72

1. At -70 ° C, 0.36 g of (3R, 4R) -4- (n-butylthio) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) ) To a solution of acetamido] -2-oxo-azetidine in 4 ml of dimethylformamide was added a solution of 0.381 g of sulfur trioxide-dimethylformamide complex in 1.43 ml of dimethylformamide, and the resulting mixture was allowed to stand at 0 ° C for two days. . Then, 0.198 g of pyridine is added and the reaction mixture is worked up as described in Example 6, 0.445 g of (3R, 4R) -4- (n-butylthio) -3- [2- (2-chloroacetamidothiazol-4-yl) - 2- (methoxyimino) acetamido] -2-oxoazetidine-1-sulfonic acid pyridinium salt.

IR spectra at? _X cm ^-1 : 3250, 1775, 1660, 1550 and 1530, 1270, 1245, 1208 and 1036.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 0.86 (m, CH ₃ ), 1.43 (m, -CH ₂ -), 2.76 (t, J = 7Hz, -CH ₂ -), 3.86 (s, CH ₃ ), 4.32 (s, -CH ₂ -), 5.13 (d, J = 6Hz, C ₄ -H), 5.34 (dd, J = 6.9Hz, C ₃ -H),

7.50 (s, part XXV), 7.97-9.00 (m, aromatic H) and 9.48 (d, J = 9Hz, NH).

2. 0.33 g of (3R, 4R) -4- (n-butylthio) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -2- A mixture of oxoazetidine-1-sulfonic acid pyridinium salt, 10 ml of Na ⁺ -formed Dowex 50W resin and 15 ml of 50% aqueous ethanol was stirred for 30 minutes, then the resin was filtered off and the filtrate was lyophilized to give 0.215 g (3R, 4R). 4- (n-butylthio) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxo-azetidine-1-sulfonic acid sodium salt was obtained.

IR Spectrum: cm- ¹ : 3270, 1792, 1656, 1550-1525, 1248, 1050 and 1036.

NMR (d _e -DMSO, ppm): 0.87 (m, _CH3), 1.45 (m, _-CH2 -), 2.76 (t, J = 7Hz, _-CH2 -); 3.88 (s, CH ₃ ), 4.34 (s, -CH ₂ -), 5.16 (d, J = 6Hz, C ₄ -H), 5.35 (dd, J = 6.9Hz, C ₃ -H),

7.51 (s, moiety XXV), 9.51 (d, J = 9Hz, NH) and 12.93 (broad s, NH).

3. Under ice-cooling, 0.17 g of (3R, 4R) -4- (n-butylthio) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamide] To a solution of the sodium salt of -2-oxoazetidine-1-sulfonic acid in 16 ml of 50% aqueous ethanol was added 0.053 g of sodium monomethyl dithiocarbamate, and the resulting mixture was stirred at room temperature for 50 minutes and then the ethanol was evaporated in vacuo. The residue was purified on a XAD-II resin column with 0.064 g of (3R, 4R) -4- (n-butylthio) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamide ] -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR nu ^ ^r _x cm ^-1: 3415,3320,1765,1662, 1525, 1270, 1250 and 1048th

NMR (d _e -DMSO, ppm): 0.88 (t, J = 7Hz, _CH3), 1.46 (m, _-CH2 -), 2.76 (t, J = 7Hz, -CH ₂ -), 3.84 (s, CH ₃ ), 5.14 (d, J = 6Hz, C ₄ --H),

5.32 (dd, J = 6.8Hz, C ₃ -H), 6.90 (s, part of XXV), 7.15 (s, NH ₂ ) and 9.37 (d, J = 8Hz). NH).

Example 73

1. At -70 ° C, 0.4 g of (3R, 4S) -4- (n-butylthio) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) To a solution of acetamido] -2-oxoazetidine in 3 ml of dimethylformamide was added 0.424 g of sulfur trioxide-dimethylformamide complex in 1.59 ml of dimethylformamide and the resulting mixture was allowed to stand at 0 ° C for two days. After addition of 0.219 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.231 g of (3R, 4S) -4- (n-butylthio) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR .nu ® * _x ^{r cm-1:} 3260, 1765, 1668.1542, 1260 and 1040th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 0.88 (m, CH 2), 1.48 (m, -CH ₂ -), 2.77 (m, -CH ₂ -), 3.87 ( s, CH ₃ ), 4.36 (s, CH ₃ ), 4.66 (dd, J = 3.8Hz, C ₃ --H), 4.80 (d, J = 3Hz, C ₄ --H), 7.38 (s, part XXV), 9.45 (d, J = 8Hz, NH) and 12.88 (s, NH).

2. Under ice cooling, 0.18 g of (3R, 4S) -4- (n-butylthio) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamide] To a solution of the sodium salt of -2-oxoazetidine-1-sulfonic acid in 15 ml of 30% aqueous ethanol was added 0.052 g of sodium monomethyldithiocarbamate, and the resulting mixture was allowed to stand at 0 ° C for 2 days. The reaction mixture was then stirred at room temperature for one hour and purified as described in Example 72, Part 3. Thus, 0.056 g of (3R, 4S) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] 4- (n-butylthio) -2-oxoazetidine The sodium salt of 1-sulfonic acid is obtained.

IR nu * ® ^r cm ^-1: 3400, 3320,1765,1662, 1530, 1270, 1250 and 1048th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 0.89 (br, CH ₃ ), 1.24-1.76 (m, -CH ₂ -), 2.68 (m, -CH ₂ -) , 3.85 (s, CH ₃ ), 4.62 (dd, J = 3.8Hz, C ₃ -H), 4.81 (d, J = 3Hz, C ₄ -H), 6.66 (s , XXV), 7.16 (s, NH ₂ ) and 9.32 (d, J = 8 Hz, NH).

Example 74

0.42 g of (3R, 4S) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4- (n-propylthiothiocarbonylthio) -2- To a solution of oxo-azetidine in 5 ml of dimethylformamide was added 0.39 g of sulfur trioxide-dimethylformamide complex at -20 ° C.

1.72 ml of dimethylformamide and the resulting mixture was stirred at 5 ° C for 2 days. After addition of 0.237 g of pyridine, the reaction mixture was worked up as described in Example 1 with 0.085 g of (3R, 4S) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido]. ] -4- (n-propylthiothiocarbonylthio) -2-oxoazetidine-1-sulfonic acid sodium salt (Compound A) and 0.119 g of the corresponding (3R, 4R) -isomer (Compound B).

Identification of Compound A:

IR spectra:? _X cm ^-1 : 3240, 1778, 1663, 1539, 1278 and 1039.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 0.97 (t,

-44189 545

J = 7Hz, CHJ, 1.68 (m, _-CH2 -), 3.36 (t, J = 7Hz, _-CH2 -), 3.93 (s, _CH3), 4.37 (s, C1CH ₂ -), 4.96 (dd, J = 2.9Hz, C ₃ -H), 5.88 (d, J = 2Hz, C ₄ -H);

7.34 (s, part XXV) and 9.58 (broad s, NH).

Identification of Compound B:

IR .nu ® ^ _x ^{r cm-1:} 3500, 3260, 1773.1668, 1540, 1270 and 1045th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 0.96 (t, J = 7Hz, CH ₃ ), 1.68 (m, -CH ₂ -), 3.36 (t, J = 7Hz, -CH ₂ -), 3.86 (s, CH 1, 4.35 (s, C ₁ - CH ₂ -), 5.58 (dd, J = 5-9Hz, C ₃ --H), 6.16 (d, J = 5Hz). , C ₄ -H),

7.18 (s, part XXV) and 9.38 (d, J = 9Hz, NH).

Example 75

At room temperature, 0.128 g of (3R) -3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4- (n-propylthiothiocarbonylthio) -2-oxo A suspension of azetidine-1-sulfonic acid sodium salt and 0.028 g of sodium monomethyl dithiocarbamate in 3 ml of 30% aqueous methanol was stirred for 2 hours and worked up as described in Example 3. Thus, 0.023 g of (3R, 4S) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (n-propylthiothiocarbonylthio) -2- The oxo-azetidine-1-sulfonic acid sodium salt (Compound A) and 0.050 g of the corresponding (3R, 4R) -isomer (Compound B) are obtained.

Identification of Compound A:

IR spectrum cm-1: 3310.1775, 1661, 1613, 1520, 1272, 1250 and 1048.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 0.97 (t, J = 7Hz, CH 2), 1.68 (m, -CH ₂ -), 3.34 (t, J = 7Hz, -CH ₂ -), 3.86 (s, CH ₃ ), 4.90 (dd, J = 2.9Hz, C ₃ --H), 5.87 (d, J = 2Hz, C ₄ --H), 6, 60 (s, XXV), 7.18 (s broad, NH) and 9.48 (d, J = 9Hz, NH).

Identification of Compound B:

IR nu ^ _x ^cm-1: 3310, 1774, 1661, 1612, 1520, 1272 and 1250th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 0.97 (t, J = 7Hz, CH ₃ ), 1.68 (m, -CH ₂ -), 3.34 (t, J = 7Hz, -CH _2- ), 3.80 (s, CH ₃ ), 5.52 (dd, J = 5.9Hz, C ₃ -H), 6.13 (d, J = 5Hz, C ₄ -H), 6, 48 (s, XXV), 7.18 (s broad, NH3 and 9.28 (d, J = 9Hz, NH)).

Example 76

0.4 g of (3S, 4S) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -3- (S) at 1-20 C To a solution of formyloxybutanamido] -2-oxoazetidine in 3 ml of dimethylformamide is added 0.432 g of sulfur trioxide-dimethylformamide complex

1.61 ml of dimethylformamide and the reaction mixture was allowed to stand at 4 ° C for two days. After addition of 0.224 g of pyridine, the reaction mixture was worked up as described in Example 1 in an amount of 0.282 g of (3S, 4R) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide). ) -3- (S) formyloxy-butylamido] -2-oxo-azetidine-1-sulfonic acid, sodium salt.

The IR spectrum nu trum ™ ^{r cm-1:} 3460, 3270, 2105, 1775, 1710, 1665, 1515, 1270, 1248, 1180, 1045th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.11 (t, J = 7Hz, CH ₃ ), 1.23 (d, J = 6Hz, CH ₃ ), 3.43 (q, J = 7Hz, -CH ₂ -), 3.40-3.80 (m, -CH ₂ -), 3.86-4.04 (m, -CH ₂ -), 4.46 (dd, J = 2.8Hz, C ₃ -H), 4.55 (dd, J = 4.8 Hz, part of formula XXVI.), 5.11 (d, J = 2Hz, _C3 -H), 5.40 (m, part formula XXVI.) 8.19 (s, CHO), 9.10 (d, J = 8Hz, NH) and 9.36 (d, J = 8Hz, NH).

2. Under ice-cooling, 0.1 g of (3S, 4R) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) 3- (S) -formyloxy] To a solution of the sodium salt of butylamido] -2-oxo-azetidine-1-sulfonic acid in 3 ml of water was added 0.57 ml of 1 N hydrochloric acid and the resulting mixture was stirred for 30 minutes. Sodium bicarbonate (0.048 g) was added to the reaction mixture, which was purified by chromatography on a column packed with XAD-II resin, 0.036 g of (3S, 4R) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo) 1-piperazinecarboxamido) -3- (S) -hydroxybutanamido] -2-oxoazetidine-1-sulfonic acid sodium salt.

IR .nu ™ ^r cm⁻¹: 3430-3300, 2115.1775, 1705, 1670, 1518, 1275, 1250 and 1048th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.08 (d, J = 6Hz, CH ₃ ), 1.10 (t, J = 7Hz, CH ₃ ), 3.42 (q, J = 7Hz, -CH ₂ -), 3.56 (m, -CH ₂ -), 3.94 (m, -CH ₂ -), 4.00-4.24 (m, part of Formula XXVI), 4.42 (dd, J = 2.8Hz, C ₃ -H), 5.15 (d, J = 2Hz, C ₄ -H);

5.18 (s, OH), 8.75 (d, J = 8Hz, NH) and 9.28 (d, J = 8Hz, NH).

Example 77

1. -20 ° C 1.25 g of (3R) -4- (2-acetamidoethylthio) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) To a solution of -acetamido] -2-oxo-azetidine in 10 ml of dimethylformamide was added a solution of 1.25 g of sulfur trioxide-dimethylformamide complex in 4.66 ml of dimethylformamide, and the reaction mixture was allowed to stand at 4 ° C for 2 days. . After the addition of 0.643 g of pyridine, the reaction mixture was refluxed

Work up as described in Example 1 on one side of (3R, 4S) -4- (2-acetamidoethylthio) -3- [2- (2-chloroacetamidothiazol-4-yl) -2-methoxy] imino) -acetamido] -2-oxo-azetidine-1-sulfonic acid sodium salt (Compound A) and on the other hand 0.336 g of the corresponding (3R, 4R) -isomer (Compound B).

Identification of Compound A:

IR spectrum cm- ¹ : 3250, 1767, 1660, 1540, 1260 and 1038.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.85 (s, CH ₃ ), 2.86 and 3.28 (both m, -CH ₂ -), 3.90 (s, CH ₃ ), δ , 37 (s, CICH ₂ -), 4.68 (dd, J = 2.8Hz, C ₃ -H), 4.86 (d, J = 2Hz, C ₄ -H), 7.41 (s, XXV) and 9.46 (d, J = 8Hz, NH).

Identification of Compound B:

IR nu ^ CIRT ^1: 3275, 1763, 1658.1540, 1270, 1050 and 1038th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm: 1.81 (s, CH ₃ ), 2.86 and 3.24 (both m, -CH ₂ -), 3.88 (s,

-451

189,545

CH 3), 4.36 (s, CH 2 Cl 3), 5.18 (d, J = 5Hz, C ₄ -H),

5.36 (dd, J = 5.8Hz, C ₃ -H), 7.51 (s, part XXV) and 9.50 (d, J = 8Hz, NH).

2. Under ice-cooling, 0.200 g of (3R, 4R) -4- (2-acetamidoethylthio) -3- [2 '(2-chloroacetanimidothiazol-4-yl) -2- (methoxyimino) acetamido] -2 To a solution of the oxoazetidine-1 sulfonic acid sodium salt (compound B) in 5 mL of water was added 0.046 g of sodium monomethyldithiocarbamate and the resulting mixture was stirred at room temperature for 2 hours and then worked up as described in Example 3. Thus, 0.081 g of (3R, 4R) -4- (2-acetamidoethylthio) -3- [2- (2-aminothiazol-4-yl) -2 (methoxyimino) acetamido] -2-oxo- yielding the sodium salt of azetidine-1-sulfonic acid.

IR nu ^ ® / ^cm-1: 3320.1762, 1658, 1522, 1270, 1048th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.80 (s, CH ₃ ), 2.82 and 3.21 (both m, -CH ₂ -), 3.84 (s, CH ₃ ), δ 17 (d, J = 5Hz, C ₄ - H), 5.33 (dd, J = 5.8Hz, C ₃ -H), 6.89 (s, part XXV.)

7.18 (bs, NH ₂ ), 7.88 (m, NH) and 9.40 (d, J = 8Hz, NH).

Example 78

0.212 g of (3R, 4S) -4- (2-acetamidoethylthio) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine A mixture of the sodium salt of -1-sulfonic acid and 0.049 g of sodium monomethyl dithiocarbamate was treated with 0.037 g of (3R, 4S) -4- (2-acetamidoethylthio) -3- [2- (2- yielding the sodium thiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine-1-sulfonic acid salt.

IR spectrum cm- ¹ : 3310, 1763, 1656, 1528, 1270, 1248, 1043.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.80 (s, CH ₃ ), 2.86 and 3.23 (both m, -CH ₂ -), 3.87 (s, CH ₃ ), δ , 82 (d, J = 2Hz, C ₄ -H), 4.64 (dd, J = 2.8Hz, C ₃ -H), 6.78 (s, part of Formula XXV), and

9.40 (d, J = 8Hz, NH).

2. A suspension of 0.45 g and 0.104 g of sodium monomethyl dithiocarbamate in 50% aqueous methanol from the pyridinium derivative obtained in Part 1 of the Example is stirred at room temperature for 30 minutes and worked up as described in Example 3. 0.113 g of (3R, 4R) -3- [2- (2-amino-thiazol-4-yl) -2- (methoxyimino) acetamido] -4-cyclohexylthio-2-oxoazetidine-1-sulfonic acid sodium salt are obtained. .

IR .nu ® * _x ^r cm 1765.1660, 1620, 1525,

1250 and 1045.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.84 (s, OCH ₃ ), 4.24 (d, J = 5Hz, C ₄ H), 5.30 (dd, J = 5.8Hz, C ₃ -H), 6.92 (s, part XXV.) and

9.32 (d, J = 8Hz, NH).

Example 80

1. If (3R, 4S) -4-cyclohexylthio-3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -2-oxo-azetidine is prepared according to Example 79. (3R, 4S) -4-Cyclohexylthio-3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxo The pyridinium salt of -azetidine-1-sulfonic acid is obtained.

IR nu f * _x ^{r cm-1:} 1765, 1670, 1540.1265, 1045th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.90 (s, OCH ₃ ), 4.36 (s, -CH ₂ -), 4.64 (dd, J = 2.8Hz, C ₃ -H). , 4.90 (d, J = 2Hz, C ₄ -H), 7.36 (s, part XXV. formula), 9.45 (d, J = 8Hz, NH).

2. The pyridinium salt prepared as described in Example 1, Part 1 was treated as described in Example 79, Part 2 with (3R, 4S) -4-cyclohexylthio-3- [2- (2-aminothiazol-4-yl) -2- (methoxy) -imino) -acetamido] -2-oxo-azetidine-1-sulfonic acid sodium salt is obtained.

IR .nu ® * _x ^{r cm-1:} 1765, 1660, 1520, 1250 and 1040th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.95 (s, OCH ₃ ), 4.89 (d, J = 2Hz, C ₄ H), 7.45 (s, part XXV) and 9.50 (d, J = 8Hz, NH).

Example 79

I. At -70 ° C, 0.552 g of (3R, 4R) -4-cyclohexylthio-3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) acetamide] -2- To a solution of oxoazetidine in 2 ml of dimethylformamide was added a solution of 0.55 g of sulfur trioxide-dimethylformamide complex in 2.1 ml of dimethylformamide, and the resulting mixture was allowed to stand at 0 ° C for 30 hours. After addition of 0.5 ml of pyridine, the reaction mixture was worked up as described in Example 6 with 0.657 g of (3R, 4R) -4-cyclohexylthio-3- [2- (2-chloroacetamidothiazol-4-yl) -2- ( methoxyimino) acetamido] -2-oxoazetidine-1-sulfonic acid, pyridinium salt.

IR nu * _"x ^{r cm-1:} 1780, 1770, 1660, 1525, 1250, 1040th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.88 (s, OCH ₃ ), 4.36 (s, -CH ₂ -), 7.52 (s, part XXV), and 9.44 (dd, J = 8Hz, NH).

Example 81

0.54 g of 3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4-fluoro-2-oxoazetidine at 70 ° C with 2 ml of dimethylformamide A solution of 0.7 g of sulfur trioxide-dimethylformamide complex in 2.6 ml of dimethylformamide was added and the resulting mixture was allowed to stand at 0 ° C for 2 days. After addition of 0.5 ml of pyridine, the reaction mixture was worked up as described in Example 1. 0.233 g of sodium salt of 3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4-fluoro-2-oxo-azetidine-1-sulfonic acid are obtained.

IR spectrum ηΰ * _χ cm ^-1 : 1780.1675, 1540, 1270, 1040.

Example 82

0.1 g of (3R, 4R) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2- (chloromethyl) -461 at -70 ° C. To a solution of 189,545 acetamido] -4-methylthio-2-oxoazetidine in 1 ml of dimethylformamide was added a solution of 0.11 g of sulfur trioxide-dimethylformamide in 0.42 ml of dimethylformamide and the resulting mixture was stirred at 0 ° C. leave for 3 days. After adding 0.3 ml of pyridine, the reaction mixture was worked up as described in Example 1, giving 0.038 g of 3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-chloromethyl]. acetamido] -4-methylthio-2-oxoazetidine-1-sulfonic acid sodium salt.

IR Spectrum: cm @ -1: 1765, 1720, 1680, 1520, 1280, 1250 and 1050.

Example 83

- 0.35 g of (3R, 4R) -4- (tert-butylthio) -3- [D2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3 (S) at 20 ° C. ) -formyloxybutanamido] -2-oxoazetidine in 3 ml of dimethylformamide was added 0.346 g of sulfur trioxide-dimethylformamide complex

A solution of 1.27 ml of dimethylformamide was added and the reaction mixture was allowed to stand at 5 ° C for two days. After adding 0.18 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.27 g of (3R, 4R) -4- (tert-butylthio) -3- [D-2- (4-ethyl-2,3-dioxo) -1-piperazinecarboxamido) -3- (S) -formyloxybutanamido] -2-oxoazetidine-1-sulfonic acid sodium salt.

IR nu * ® ^r cm⁻¹: 3475,3280,1760,1712,

1675, 1520, 1275 and 1250.

NMR (d _e -DMSO, ppm): 0.88 (m, CH), 1.11 (t, J = 7Hz, CH₂), 1.20 to 1.66 (m, CH _3, -CH ₂ -), 2.74 (t, J = 7Hz, _-CH2 -), 3.42 (q, J = 7Hz, _-CH2 -), 3.60 (m, _-CH2 -), 3.94 (m, _-CH2 -), 4.67 (dd, J = 4.8 Hz, part of formula XXVI.), 5.06 to 5.40 (m, C ₃ -H, C ₄ -Η, formula XXVI. part), 8.16 (s, CHO), 9.11 (d, J = 8Hz, NH), 9.37 (d, J = 8Hz, NH).

Example 84

0.45 g of (3S, 4R) -4-azido-3- [D-2- (2-oxo-imidazolidin-1-ylcarboxamido) -2-phenylacetamido] -2-oxo at -20 ° C. To a solution of azetidine in 4 ml of dimethylformamide was added 0.55 g of sulfur trioxide dimethylformamide complex in 2.1 ml of dimethylformamide, and the resulting reaction mixture was allowed to stand at 5 ° C for 2 days. To the reaction mixture was added 0.29 g of pyridine, and the reaction mixture was worked up as described in Example 1, in the amount of 0.12 g of (3S, 4S) -4-azido-3- [D-2- (2-oxo-3-sulfonate). imidazolidin-1-yl-carboxamido) -2-phenylacetamido] -2-oxo-azetidine-1-sulfonic acid disodium salt.

IR nu * ® ^{r cm-1:} 3470, 3300,1770,1660, 1520, 1245 and 1050th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 3.30 (m, -CH ₂ -), 3.70 (m, -CH ₂ -), 5.12 (dd,

J = 5.8Hz, C ₃ -H), 5.35 (d, J = 5Hz, C ₄ -H), 5.54 (d, J = 8Hz, Part XXVI), 7.20-7, 60 (m, aromatic H), 9.07 (d, J = 8Hz, NH) and 9.24 (d, J = 8Hz, NH).

Example 85

0.45 g of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4- To a solution of isopropylthio) -2-oxoazetidine in 5 ml of dimethylformamide was added a solution of 0.48 g of sulfur trioxide-dimethylformamide complex in 1.82 ml of dimethylformamide, and the resulting mixture was allowed to stand at 5 ° C for two days. forget it. After addition of 0.25 g of pyridine, the reaction mixture was worked up as described in Example 1 with 0.45 g of (3R, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2-methoxyimino). ) -acetamido] -4- (isopropylthio) -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR spectra:? / Cm @ ^-1 : 3260.2950, 1768, 1668, 1542, 1250 and 1048.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.19 and 1.26 (both d, J = 6Hz, CH ₃ ), 3.3 (m, --CH =),

3.88 (s, CH ₃ ), 4.35 (s, CICH ₂ -), 5.24 (d, J = 5Hz, C ₄ -H), 5.39 (dd, J = 5.9Hz, C ₃ H), 7.48 (s, part XXV) and 9.43 (d, J -. 9Hz, NH).

2.0.275 g of (3R, 4R) -3- [2- (2-Chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4- (isopropylthio) 2-oxo-azetidin-1 A solution of sodium sulfonic acid sodium salt and 0.068 g of sodium monomethyl dithiocarbamate in 5 ml of 40% aqueous methanol was stirred at room temperature for 2 hours and worked up as described in Example 3. Thus, 0.077 g of (3R, 4R) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (isopropylthio) -2-oxoazetidine-1-sulfonic acid is obtained. sodium salt is obtained.

IR .nu ® * _x ^r cm ^"1: 3310, 1761, 1663, 1618, 1525, 1240 and 1045th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.20 and 1.26 (both d, J = 6Hz, CH ₃ ), 3.3 (m, --CH =),

3.84 (s, CH ₃ ), 5.22 (d, J = 5Hz, C ₄ H), 5.36 (dd, J = 5.9Hz, C ₃ H), 6.88 (s , Part XXV),

7.15 (bs, NH ₂ ) and 9.33 (d, J = 9Hz, NH).

Example 86 - 0.26 g of (3R, 4S) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4 at 20 ° C To a solution of (isopropylthio) -2-oxo-azetidine in 2 ml of dimethylformamide was added a solution of 0.28 g of sulfur trioxide-dimethylformamide in 1.1 ml of dimethylformamide and the resulting mixture was allowed to stand at 5 ° C for two days. . After addition of 0.145 g of pyridine, the reaction mixture was worked up as described in Example 6, 82 mg of (3R, 4S) -3- [2- (2-chloroacetamidothiazol-4-yl) -2-methoxyimino) acetamide ] -4- (isopropylthio) -2-oxo-azetidine-1-sulfonic acid pyridinium salt. To a solution of this product in 10 ml of 50% aqueous methanol was added sodium bicarbonate until the solution was adjusted to pH 7, and then 0.08 g of sodium monomethyl dithiocarbamate was added to the reaction mixture. Stir at room temperature for 1.5 hours. The reaction mixture was then worked up as described in Example 3 for (3R, 4S) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (isopropylthio) -2-oxo. azetidine-1-sulfonic acid sodium salt.

-471

189,545

R spectrum λmax _x cm -1: 3320, 1763, 1670, 1618, 1523, 1242 and 1045.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.20 and 1.28 (both d, J = 6Hz, CH ₃ ), 3.84 (s, CH ₃ ), 4.60 (dd, J = 2). , 9Hz, _C3 -H), 4.89 (d, J = 2Hz, C ₄ -H);

6.66 (s, part of Formula XXV), 7.16 (broad s, NH ₂ ) and

9.34 (d, J = 9Hz, NH).

Example 87

1. At -20 ° C, 0.4 g of (3 S, 4 R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4 ( To a solution of ethoxycarbonylmethoxy) -2-oxoazetidine in 3 ml of dimethylformamide was added 0.41 g of sulfur trioxide-dimethylformamide complex in 1.53 ml of dimethylformamide and the resulting mixture was stirred at 5 ° C. leave for two days. After addition of 0.212 g of pyridine, the reaction mixture was worked up as described in Example 1, in the amount of 0.35 g of (3S, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino). acetamido] -4- (ethoxycarbonylmethoxy) -2-oxoazetidine-1-sulfonic acid, sodium salt.

R spectrum nu ™ ^r cm '': 3400, 3250, 1772, 1740, 1670, 1540, 1262 and 1,042th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.20 (t, J = 7Hz, CH ₃ ), 3.87 (s, CH ₃ ), 4.15 (q, J = 7Hz, --CH ₂ -). ), 4.33 (s, - CH ₂ -), 4.45 (AB q, J = 24,39Hz, _-CH2 -), 5.18 (dd, J = 5.9Hz, C ₃ -H), 5.38 (d, J = 5Hz, _C4 -H), 7.63 (s, part XXV. formula), 9.43 (d, J = 9Hz, NH) and 12.80 (br s, NH) .

2. To a solution of the compound obtained in Part 1 in 0.2 g of water (7 ml) was added 0.052 g of sodium monomethyl dithiocarbamate under ice-cooling, and the resulting mixture was stirred at room temperature for 50 minutes. Chromatography on a column packed with XAD-II resin under ice-cooling gave 0.053 g of (3S, 4R) -3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4 (ethoxy) -carbonylmethoxy) -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR .nu ™ ^r cm '': 3400,3320,1772,1735, 1665, 1522, 1270, 1238, 1128 and 1045th

NMR (d _e -DMSO, ppm): 1.22 (t, J = 7Hz, _CH3), 3.82 (s, _CH3), 4.14 (q, J = 7 Hz, - CH ₂ - ), 4.48 (s, --CH ₂ -), 5.15 (dd, J = 5.8Hz, C ₃ --H), 5.36 (d, J = 5Hz, C ₄ --H), 6, 97 (s, portion XXV), 7.10 (s, NH ₂ ) and 9.29 (d, J = 8Hz, NH).

Example 88

0.4 g of (3S, 4R) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamide) -3- (S) at 1-20 ° C. To a solution of formyloxybutanamido] -2-oxoazetidine in 3 ml of dimethylformamide was added a solution of 0.433 g of sulfur trioxide-dimethylformamide complex in 1.62 ml of dimethylformamide, and the resulting mixture was stirred at 0 ° C for two days. let it change. After addition of 0.224 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.202 g of (3S, 4S) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) - 3- (S) 46 formyloxybutanamido] -2-oxoazetidine-1-sulfonic acid sodium salt.

R spectrum nu ^ ¹ JCM 3450, 1770, 1708, 1670,

1515, 1275, 1185 and 1048.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 7Hz, CH ₃ ), 1.24 (d, J = 6Hz, CH ₃ ), 3.41 (q, J = 7Hz, -CH ₂ -), 3.56 (m, -CH ₂ -), 3.93 (m,

CII ₂ ), 4.64 (dd, J = 3.9Hz, portion XXVI), 5.08 (dd, J = 5.8Hz, C ₃ -H), 5.37 (m, portion XXVI). ), 5.43 (d, J = 5Hz, C ₄ H), 8.17 (s, CHO), 9.10 (d, J = 8Hz, NH), and 9.36 (d, J = 9Hz, NH).

2. To a solution of the compound obtained in Part 1 in 0.15 g of water (3 ml) was added with ice-cooling 1N hydrochloric acid (0.86 ml), and the resulting mixture was stirred at room temperature for 1.5 hours, followed by 0.072 g of sodium bicarbonate. 84 mg of (3S, 4S) -4-azido-3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -3- (84 mg) were added as a result of chromatography on a column packed with XAD-II resin. The (S) -hydroxybutanamido] -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

R spectrum nu ^ 'ciu ^1: 3440, 3300, 1772, 1705, 1670, 1510, 1270 and 1,192th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 7Hz, CH ₃ ), 1.14 (d, J = 6Hz, CH ₃ ), 3.42 (q, J = 7Hz, -CH ₂ -), 3.56 (m, -CH ₂ -), 3.92 (m, -CH ₂ -), 4.07 (m, part of Formula XXVI), 5.13 (dd, J = 5.8Hz, C ₃ -H), 5.40 (d, J = 5Hz, _C4 -H), 8.78 (d, J = 8Hz, NH) and 9.24 (d, J = 8Hz, NH ).

Example 89

In the same manner as in Example 88, Part 1, 0.4 g of (3S, 4S) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -4 - (Ethoxycarbonylmethoxy) -2-oxoazetidine (0.07 g) (3S, 4S) -3- [2- (2-Chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamide] - The sodium salt of 4- (ethoxycarbonylmethoxy) -2-oxoazetidine-1-sulfonic acid can be prepared.

IR .nu ™ ^{r cm-1:} 3420.1772, 1738, 1668, 1640, 1270, 1230 and 1035th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.21 (t, J = 7Hz, CH ₃ ), 3.90 (s, CH ₃ ), 4.13 (q, J = 7Hz, -CH ₂ -). ), 4.36 (s, -CH ₂ -), 4.49 (s, -CH ₂ -),

4.66 (dd, J = 2.8Hz, C ₃ -H), 5.23 (d, J = 2Hz, C ₄ -H), 7.42 (s, Part XXV. Formula) and 9.38 ( d, J = 8Hz, NH).

Example 90

0.262 g of (3S, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) acetamido] -3-methoxy-4- To a solution of methylthio-2-oxoazetidine in 3 ml of dimethylformamide was added a solution of 0.287 g of sulfur trioxide-dimethylformamide complex in 1.07 ml of dimethylformamide and the resulting mixture was allowed to stand at 0 ° C for two days. After addition of 0.15 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.254 g of (3S, 4R) -3- [2- (2-chloroacetamidothiazol-4-yl) -2- (methoxyimino) - acetamido] -3-methoxy-4-methylthio-2-oxo-azetidine-1-sulfonic acid, sodium salt.

-481

189,545

IR spectrum at ¹ : 3230, 1770, 1675, 1540, 1260 and 1045.

2. To a solution of 0.158 g of the compound obtained in Part 1 in 2 ml of water is added 43 mg of sodium monomethyl dithiocarbamate under ice-cooling, and the resulting mixture is stirred at room temperature for one hour. The reaction mixture was then worked up as described in Example 3, 78 mg of (3R, 4R) -3- [2- (2-aminothiazol-4-yl) -2-methoxyimino) acetamido] -3-methoxy Yielding the sodium salt of 4-methylthio-2-oxoazetidine-1-sulfonic acid.

IR .nu ™ ^{r cm-1:} 1773, 1670.1620, 1525, 1250 and 1050th

Example 91

0.4 g of (3S, 4R) -4-azido-3- [2- (4-ethyl-2,3-dioxo-piperazinecarboxamido) -4-pentinamido] -2-oxo-azetidine at 70 ° C in 3 mL of dimethyl To a solution of -formamide was added a solution of sulfur trioxide-dimethylformamide complex (0.47 g) in dimethylformamide (1.76 ml) and the resulting mixture was allowed to stand at 0 ° C for two days. After addition of 0.244 g of pyridine, the reaction mixture was worked up as described in Example 1, 0.297 g of (3S, 4S) -4-azido-3- [2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -4- pentinamido] -2-oxo-azetidine-sulfonic acid, sodium salt.

IR .nu ™ ^{r cm-1:} 3470,3270,2110,1775, 1708, 1670, 1510, 1280 to 1240 and the 1048th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.10 (t, J = 7Hz, CH ₃ ), 2.70 (m, -CH ₂ -), 2.84 (m, HC =), 3, 41 (q, J = 7Hz, _-CH2 -), 3.57 (m, _-CH? -), 3.92 (m, _-CH? -), 4.53 (m. When sub-formula XXVI) 5.09 and 5.13 (both dd, J = 5.8Hz, C ₃ -H), 5.44 and 5.47 (both dd, J = 5Hz, C ₄ -H), 8.99 and 9, O 2 (both d, J = 8Hz, NH) and 9.42 (d, J = 8Hz, NH).

Example 92

-70 ° C 1 g of (3R) -4- (2-acetamidoethylthio) -3- [D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) 2-phenylacetamide To a solution of 2-oxo-azetidine in 5 ml of dimethylformamide was added a solution of 0.9 g of sulfur trioxide-dimethylformamide complex in 3.4 ml of dimethylformamide and the resulting mixture was allowed to stand at 0 ° C for two days. After addition of 0.47 g of pyridine, the reaction mixture is worked up as described in Example I, 0.402 g of (3R, 4R) -4- (2-acetamidoethylthio) -3- [D-2- (4-ethyl-2,3) -dioxo-1-piperazinecarboxamido) 2-phenylacetamido] -2-oxoazetidine-1-sulfonic acid sodium salt (Compound A) and 0.132 g of the corresponding (3R, 4S) -isomer (Compound B).

Identification of Compound A:

IR: cm- ¹ : 3280, 1768, 1712, 1670, 1505, 1272, 1243 and 1042.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.08 (t, J = 7Hz, CH 3, 1.78 (s, CH ₃ ), 3.40 (q, J = 7Hz, -CH ₂ -), 5.05 (d, J = 5Hz, C ₄ - H), 5.26 (dd, J = 5.8Hz, C ₃ -H), 5.58 (d, J = 8Hz, XXVI part thereof.); 9.27 (d, J = 8Hz, NH) and 9.79 (d, J = 8Hz, NH).

Identification of Compound B:

IR spectrum: cm ^-1 : 3290, 1765, 1710, 1670, 1503, 1250, 1185, 1043.

NMR (d _e -DMSO, ppm): 1.09 (t, J = 7Hz, CHJ, 1.78 (s, CHJ, 3.40 (q, J = 7Hz, _-CH2 -) 4, 57 (dd, J = 3.8Hz, C ₃ -H), 4.70 (d, J = 3 Hz, C ₄ -H), 5.43 (d, J = 8 Hz, sub-formula XXVI.), 9, 32 (d, J = 8Hz, NH) and 9.77 (d, J = 8Hz, NH).

Example 93

1. At -20 DEG C. 0.6 g of (3S, 4R) -4-azido-3- [2- (2-formamidothiazol-4-yl) -2- (methoxyimino) acetamide] -2- To a solution of oxoazetidine in 4 ml of dimethylformamide was added 0.814 g of sulfur trioxide dimethylformamide complex in 3.04 ml of dimethylformamide, and the resulting mixture was allowed to stand at 0 ° C for two days. After addition of 0.422 g of pyridine, the reaction mixture was purified as described in Example 1 with 0.571 g of (3S, 4S) -4-azido-3- [2- (2-formamidothiazol-4-yl) -2- (methoxyimino). -acetamido] -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR nu ^ JCM ^1: 3480, 3280, 2112, 1775, 1660, 1540, 1280, 1242 and 1053rd

NMR (d _e -DMSO, ppm): 3.90 (s, CHJ, 5.21 (dd, J = 2.8Hz, C ₃ -H), 5.45 (d, J = 5 Hz, _C4 -H), 7.42 (s, moiety XXV), 8.50 (s, CHO), 9.50 (d, J = 8Hz, NH), and 12.55 (s, NH).

2. To 0.25 g of the compound obtained in Part 1 is added 1.7 ml of 1N hydrochloric acid solution and 2 ml of methanol, and the resulting mixture is stirred at room temperature for 2.5 hours. Sodium bicarbonate (0.144 g) was then added under ice-cooling as crystals precipitated. By separating them by filtration, 0.074 g of (3S, 4S) -4-azido-3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -2-oxoazetidine -1-sulfonic acid is obtained.

IR nu ^ ^r cm 3395, 2125, 1795, 1660, 1528, 1275 and 1055th

NMR (d ₆ -DMSO, ppm): 3.95 (s, CHJ, 5.18 (dd, J = 5.8Hz, C ₃ -H), 5.51 (d, J = 5 Hz, _C4 - H), 7.01 (s, part of Formula XXV), 9.62 (d, J = 8Hz, NH).

Example 94

I. -20 ° C 0.774 g of 4- (2-acetamidoethylthio) -3- {2- (2-chloroacetamidothiazol-4-yl) -2- [2-oxo-3- (thiophene). To a solution of 3-aldimino) imidazolidin-1-ylcarboxamido] acetamido} -2-oxoazetidine in 7 ml of dimethylformamide was added 0.54 g of sulfur trioxide-dimethylformamide complex in 2.03 ml of dimethylformamide, the resulting reaction mixture was allowed to stand at 5 ° C for two days. After addition of 0.280 g of pyridine, the reaction mixture was worked up as described in Example 1 to give 0.107 g of a mixture of the cis and trans isomers of 4- (3-acetanedioethylthio) -3- (2-chloroacetamidothiazole). 4-yl) -2- [2-oxo-3- (thiophene-3aldoiminoj-imidazolidin-1-yl-carboxamido] -aceta47

-491

189,545 mido} -2-oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR spectrum cm- ¹ : 3300, 1761, 1722, 1670, 1523, 1268, 1228 and 1045.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.80 (s, CH 3, 4.34 (s, ClCH ₂ -), 5.10 (dd, J = 5.8Hz, C ₃ -H), δ , 51 and 5.64 (both d, J = 8Hz, portion XXVI), 7.19 and 7.25 (both s, portion XXV), 7.4-7.65 (m, aromatic H) , 7.85 and 7.89 (both s, = CH-), 8.92 and 9.02 (both d, J = 8Hz, NH).

2. To a solution of 80 mg of the compound obtained in Part 1 in 4 ml of water is added 14 mg of sodium monomethyl dithiocarbamate under ice-cooling, and the reaction mixture is stirred at room temperature.

After stirring for 3.5 hours, it was worked up as described in Example 3. Thus, 24.3 mg is obtained as a mixture of the cis and trans isomers

4- (2-acetamido-ethylthio) -3- {2- (2-aminothiazol-4-yl) -2- [2-oxo-3-thiophen-3-aldoimino) imidazolidin-l-ylcarboxamido] acetamido } -2-oxo-azetidine-1-sulfonic acid sodium salt is obtained.

IR nu ^ ^{r cm-1:} 3300, 1760, 1720, 1660, 1510, 1268, 1225 and 1043rd

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.79 and 1.81 (both s, CH 3, 3.83 (broad s, -CH ₂ -), 4.62 (dd, J = 2.8 Hz, C ₃ -H), 4.83 (d, J = 2Hz, C ₄ -H);

5.12 (dd, J = 5.8Hz, C ₃ -H), 5.30 (d, J = 5Hz, C ₄ -H), 5.40 and 5.43 (both d, J = 8Hz, XXVI ), 6.54 and 6.62 (both s, XXV), 7.4-7.65 (m, aromatic H), 7.86 and 7.89 (both s, = CH-- ), 8.84 and 8.88 (both d, J = 8Hz, NH).

Example 95

1. At -20 ° C, 0.43 g of (3R, 4R) -4- (2-acetamidoethylthio) -3- {2- (2-chloroacetamidothiazol-4-yl) -2- [methyl] To a solution of 1- (2-trimethylsilyl-ethoxycarbonyl) -ethoxyimino] -acetamido} -2-oxo-azetidine in 2 ml of dimethylformamide was added a solution of 0.55 g of sulfur trioxide-dimethylformamide in 2 ml of dimethylformamide. and then allowed to stand at 0 ° C for 3 days.

The reaction mixture was then treated with 0.5 g of pyridine and then concentrated under reduced pressure. Methanol (4 mL) was added to the residue, and the resulting solution was mixed with 0.6 g of tetra-n-butylammonium fluoride. The mixture was evaporated and the residue was purified by column chromatography (0.63 g) with (3R, 4R) -4- (2-acetamidoethylthio) -3- {2- (2-chloroacetamidothiazol-4-yl) -2 - [1-methyl-1- (2-trimethylsilyl-ethoxycarbonyl) -ethoxyimino] -acetamido} -2-oxo-azetidine-1-sulfonic acid tetra-n-butylammonium salt is obtained.

2. To a solution of the compound prepared in the preceding paragraph in 0.62 g of 2 ml of dimethylformamide was added 0.096 g of sodium monomethyl dithiocarbamate in 0.3 ml of water and the resulting mixture was stirred at 25 ° C for 15 minutes.

To the reaction mixture was then added 0.6 g of tetra-n-butylammonium fluoride, followed by stirring at 25 ° C for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (20 mL). The resulting solution

Extract twice with 5 ml of water and add 8 ml of Dowex 50W H ⁺ resin to the combined extract and stir for 15 minutes. The resin is then filtered off and the filtrate is purified by chromatography on a column containing XAD-II resin to give (3R, 4R) -4- (2-acetamidoethylthio) -3- [2- (2-aminothiazol-4-yl) (0.044 g). 1) -2- (1-Carboxy-1-methyl-ethoxyimino) -acetamido] -2-oxo-azetidine-1-sulfonic acid was obtained.

IR .nu ® ^ _x ^r cm 1765, 1630, 1540.1260, 1040th

NMR (d _é -DMSO, ppm): 1.50 (s, CHJ, 1.80 (s, COCHJ, 2.84 (t, J = 6Hz, -SCH ₂ -), 3.22 (m, —CH ₂ -), 5.21 (d, J = 4Hz, C ₄ H), 5.34 (dd, J = 4.8Hz, C ₃ H), 7.10 (s, part XXV). ), 7.80-8.00 (m, NH) and 9.38 (d, J = 8Hz, NH).

Example 96

1. 0.58 g of (3R, 4R) -4-methylthio-3- {2- (2-trityl-aminothiazol-4-yl-2- [1-methyl-1- (2-trimethylsilyl-ethoxycarbonyl)] To a solution of -ethoxyimino] -acetamido} -2-oxoazetidine in 2 ml of dimethylformamide was added 0.6 g of tetra-n-butylammonium fluoride, and the resulting mixture was stirred for 30 minutes and then concentrated under reduced pressure. The residue was dissolved in 2 ml of dimethylformamide and a solution of 0.55 g of sulfur trioxide-dimethylformamide complex in 2 ml of dimethylformamide was added at -70 ° C. After standing for 2 days, pyridine (0.5 g) was added and evaporated under reduced pressure to give a residue, which was dissolved in 50% aqueous methanol and treated with 10 ml of Dowex 50 H ⁺ resin. After stirring for 30 minutes, the filtrate is filtered and enough sodium bicarbonate is added to bring the filtrate to pH 6.5. Purify by chromatography on a column packed with XAD-II resin, 0.24 g of (3R, 4R) -4-methylthio-3- [2- (2-tritylaminothiazol-4-yl) -2- (1-carboxylate). -methylethoxyimino) -acetamido] -2-oxo-azetidine-1-sulfonic acid disodium salt.

IR Spectrum: cm ^-1 : 1760.1670, 1590.1525, 1270, 1050.

NMR (d ₆ -DMSO, ppm): 1.38 (s, CHJ, 1.45 (s, CHJ, 2.14 (s, SCHJ, 5.03 (d, J = 4Hz, _C4 -H ), 5.30 (dd, J = 4.8Hz, C ₃ -H),

6.70 (s, part XXV), 7.20-7.45 (m, aromatic H), 8.70 (broad s, NH) and 11.04 (d, J = 8 Hz, NH).

2. To a solution of the compound obtained in Part I (0.19 g) in 3 ml of 50% aqueous methanol was added 0.5 ml of 1 N hydrochloric acid and the resulting mixture was stirred at 25 ° C for 3 hours. Evaporation of the methanol under reduced pressure yields triphenylcarbinol which is filtered off. The filtrate was purified by column chromatography on XAD-II resin to give 0.09 g of (3R, 4R) -4-methylthio-3- [2- (2-aminothiazol-4-yl) -2- (1-50

189,545 Carboxy-1-methyl-ethoxyimino) -acetamido] -2-oxoazetidine-1-sulfonic acid is obtained.

IR spectrum ν cm ^-1 : 1760, 1630, 1540, 1260 and 1040.

Nuclear Magnetic Resonance Spectrum (D ₂ O, external standard, ppm): ^δ

1.64 (s, CH 3, 2.35 (s, SCH ₃ ), 5.50 (d, J = 5Hz, C ₄ -H), 5.60 (d, J = 5Hz, C ₃ -H), 7.30 (s, part XXV).

Example 97

1. At -20 ° C, 0.710 g of 3- [2- (2-chloroacetamidothiazol-4-yl) -2-methoxyimino) acetamido] -4- (2-formamidoethylthio) -2-oxoazetidine 3 ml of dimethyl formamide in ¹⁵ was added a solution of 0.77 g of sulfur trioxide - dimethylformamide complex in 3 ml of dimethylformamide was added and allowed the mixture to stand at 4 ° C for 2 days. After adding 0.4 g of pyridine in ²⁰ reakcióele- mixture it was worked up as described in Example 1, 0.332 g of a mixture of cis and trans isomers of 3- [2- (2-chloroacetamide-4-thiazolyl) -2- (methoxyimino) acetamido] -4- (2-formamidoetiltio) -2-azetidinone-1-sulfonic acid sodium salt to yield ^25.

IR spectrum cm- ¹ : 3450, 3250, 1761, 1660, 1535, 1250, 1042.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.8-3.1 (m, -CH ₂ -), 3.5-3.8 (m, -CH ₂ -), 3.90 (s, CHJ, ³⁰

4.38 (s, CICHj-), 4.75 (dd, J = 2.8 Hz, trans C H _3), 7.42 and 7.52 (both s, Part XXV. Formula), 5.02 ( d, J = 2 Hz, trans C ₄ -H), 5.34 (dd,

J = 5.8Hz, Cis (C ₃ H), 9.46 (d, J = 8Hz, NH) and

8.74 (s, CHO). ³⁵

2. A solution of 0.273 g and 0.064 g of sodium monomethyl dithiocarbamate in 2 ml of water from the compound obtained in Part 1 was stirred at room temperature for 1 hour and worked up as described in Example 3. Thus 0.110 g of 3- [2- (2-aminothiazol-4-yl) -2- (methoxyimino) acetamido] -4- (2-formamidoethylthio) -2- isomeric mixture of cis and ⁴⁰ trans isomers. The oxoazetidine-1-sulfonic acid sodium salt is obtained.

IR .nu ™ ^{r cm-1:} 3430,3310,1766,1660, 1522 ^45, 1240 and 1,052th

NMR (d ₆ -DMSO, ppm): 2.7-3.0 (m, _-CH2 -), 3.86 (s, CHJ, 5.00 (d, J = 2 Hz, trans C ₄ - H), 5.24 (d, J = 2Hz, trans C ₃ -H), 5.25 (d,

J = 5Hz, cis C ₄ -H), 5.28 (dd, J = 5.8Hz, cis C ₃ -H), 6.78 and 6.96 (both s, part of Formula XXV), 8.69 and 8.70 (both s, CHO) and 9.38 (d,

J = 8Hz, NH).

Example 98

0.3 g of (3R, 4R) -4- (Z-2-acetamidovinylthio) -3- (2- (2-chloroacetamido) -2- (methoxyimino) acetamide] at -20 ° C To a solution of oxo-azetidine in 3 ml of dimethylformamide ⁶⁰ was added a solution of 0.299 g of sulfur trioxide-dimethylformamide complex in 1.17 ml of dimethylformamide and the resulting mixture was allowed to stand at 0 ° C for two days. after ⁶⁵ g of pyridine reakcióele- administering the mixture was worked up as described in Example 1, 0.071 g of (3R, 4R) -4- (Z-2-acetamido vinylthio) -3- [2- (2-acetamido) -2 - (methoxyimino) acetamido] -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR spectrum: cm- ¹ : 3470, 3280, 1768, 1660, 1620, 1545, 1260 and 1050.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 1.98 (s, CH 3), 3.88 (s, CH 3, 4.36 (s, -CH ₂ -), 5.11 (d, J = 5Hz, C ₄ - H), 5.32 (d, J = 8Hz, part formula XXIX), 5.36 (dd, J = 5.8Hz, C ₃ -H), 6.97 (dd, J = 8. 10Hz, part XXX), 7.48 (s, part XXV), 9.42 (d, J = 8Hz, NH) and 9.49 (d, J = 10Hz, NH).

Example 99

1. At -20 ° C, 1.4 g of 3- [2- (2-chloroacetamido-thiazol-4-yl) -2- (methoxyimino) -acetamido] -4- [2- (4-nitro- To a solution of benzyloxycarboxamidoethyl) thio] -2-oxoazetidine in 10 ml of dimethylformamide was added a solution of 1.37 g of sulfur trioxide-dimethylformamide complex in 4.13 ml of dimethylformamide, and the reaction mixture was stirred at 4 ° C. Let C stand for 2 days. After addition of 0.76 g of pyridine, the reaction mixture was worked up as in Example 1, in the form of a mixture of cis and trans isomers of 1.1 g of 3- [2- (2-chloroacetamidothiazol-4-yl) -2 - (methoxyimino) acetamido] -4- [2- (4-nitrobenzyloxycarboxamido) ethylthio] -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR spectrum cm- ¹ : 3250, 1792, 1672, 1700, 1685, 1656, 1510, 1344, 1250 and 1038.

2. A solution of 0.688 g and 0.142 g of sodium monomethyl dithiocarbamate in 4.5 ml of dimethylformamide in 0.3 ml of water was stirred at room temperature for 5 hours, then the solvent was distilled off and the residue was evaporated.

Purified as in Example 3, 0.324 g of (3R, 4R) -3- [2- (2-aminothiazol-4-yl) -2- (2-methoxyimino) acetamido] -4- [2- (4-nitrobenzyloxycarboxamido) ethylthio] -2-oxoazetidine-1-sulfonic acid, sodium salt.

IR .nu ® ^ ^r _x cm⁻¹: 3320, 1765, 1708.1670, 1608, 1517, 1347, 1250 and 1048th

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 2.7-3.0 (m, -CH ₂ -), 3.1-3.5 (m, -CH ₂ -), 3.84 (s, CHJ,

5.18 (s, --CH ₂ -), 5.24 (d, J = 5Hz, C ₄ --H), 5.30 (dd, J = 5-8Hz, C ₃ --H), 6.89 ( s, XXV), 7.60 and 8.20 (both d, J = 9Hz, aromatic H) and 9.39 (d, J = 8Hz, NH).

3. Dissolve 0.257 g of the compound in Part 2 in a mixture of 6 ml of tetrahydrofuran and 4 ml of pH 7 buffer and add 0.250 g of 10% palladium on carbon and the resulting mixture under a stream of hydrogen for 30 minutes. stirred. The solid is filtered off, the tetrahydrofuran is distilled off from the filtrate and the residue is purified by chromatography on a column packed with XAD-II resin to give 0.1 g of (3R, 4R) -3- [2- (2-aminothiazol-4-yl) -2 - (methoxyimino) acetamido] -4- (2-aminoethylthio) -2-oxoazetidine-1-sulfonic acid, sodium salt. .

-511

189,545

IR nu * ® ^{r cm-1;} 3310,3200,1769,1660, 1610, 1525, 1240 and 1040.

NMR (d _e -DMSO, ppm): 2.8-3.3 (m, -CHj-), 3.85 (s, _CH3), 5.23 (d, J = 5Hz, C ₄ - H);

5.32 (dd, J = 5.8Hz, C ₃ H), 6.86 (s, part of XXV), 7.13 (broad s, NH ₂ ), 7.76 (s s, NH _2). ) and

9.40 (d, J = 8Hz, NH).

Example 100

0.144 g of (3R, 4R) -4- (2-acetamidoethylthio) -3- [2- (2-formamidothiazol-4-yl) -2- (1-sodium thetrazol-5-one) at -20 ° C. To a solution of 1-methoxyimino) -acetamido] -2-oxoazetidine in 1.5 ml of dimethylformamide is added a solution of 0.285 g of sulfur trioxide-dimethylformamide complex in 0.86 ml of dimethylformamide, and the reaction mixture is stirred at 0 ° C. After stirring for 3 days, after adding 0.12 ml of pyridine, the reaction mixture was worked up as described in Example 1, 0.120 g of (3R, 4R) -4- (2-acetamidoethylthio) -3- [2- (2- formamidothiazol-4-yl) -2- (tetrazol-5-ylmethoxyimino) acetamido] -2-oxoazetidine-1-sulfonic acid sodium salt.

IR spectrum ν cm ^-1 : 1765, 1655, 1545, 1270 and 1050.

Nuclear Magnetic Resonance Spectrum (d 6 -DMSO, ppm): 1.83 (s, CH ₃ ), 5.18 (d, J = 5Hz, C ₄ H), 5.30 (s, --CH ₂ -),

5.36 (dd, J = 5.8Hz, C ₃ H), 7.46 (s, part of XXV), 8.1-8.35 (m, NH), 8.52 (s, CHO). ) and 9.98 (d, J = 8Hz, NH).

Example 101

1. To a solution of (3S, 4R) -4-azido-3- (2-trimethylsilylethoxycarboxamido) -2-oxoazetidine (1.085 g) in dimethylformamide (ml) at -70 ° C is added with stirring, 1.225 g of sulfuric acid. solution of trioxide-dimethylformamide complex in 4.8 ml of dimethylformamide and the resulting mixture was allowed to stand at 0 ° C for 60 hours.

After addition of 0.632 g of pyridine, the solvent was distilled off under reduced pressure and the residue was dissolved in a solution of 2.22 g of tetra-n-butylammonium chloride in 10 ml of dichloromethane. The resulting solution was then purified by silica gel column chromatography (eluent: ethyl acetate: chloroform: methanol = 4: 4: 1). 2.3 g of (3S, 4R) -4-azido-3- (2-trimethylsilyl-ethoxycarboxamido) -2-oxoazetidine-1-sulfonic acid tetra-n-butylammonium salt are obtained.

IR .nu £ ® ^{r cm-1:} 2110,1780,1720,1670, 1250th

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , ppm): 0.03 (s,

Si (CH ₃ ) ₃ ), 0.90 (t, J = 6Hz, CH ₃ ), 2.10-2.80 (m, -CH ₂ -), 3.00-3.30 (m, -CH ₂ -), 4.20 (t, J = 8Hz, -CH ₂ O-), 4.90 (d, J = 4Hz, _C4 -H);

5.20 (dd, J = 4.8Hz, C ₃ -H) and 6.20 (d, J = 8Hz, NH).

Example 102

At -20 ° C 0.8 g of (3S, 4R) -4-azido-3- {2- (2-tritylaminothiazol-4-yl) -2- [1-methyl-1- (2-trimethyl) -Silylethoxycarbonyl) -ethoxyimino-N-acetamido} -2-oxoazetidine To a solution of 0.505 g of sulfur trioxide-dimethylformamide complex in 4.98 ml of dimethylformamide was added a solution of 0 ° C. leave for 2 days. After addition of 0.26 g of pyridine and diethyl ether, the reaction mixture was worked up as described in Example 1 to give 0.673 g of (3S, 4S) -4-azido-3- {2- (2-tritylaminothiazol-4-yl). ) -2-1-methyl-1- (2-trimethylsilyl-ethoxycarbonyl) -ethoxyimino] -acetamido} -2-oxo-azetidine-1-sulfonic acid sodium salt.

IR Spectrum? Cm ^-1 : 3380, 2115, 1778, 1728, 1676, 1512, 1282, 1245 and 1050.

Nuclear Magnetic Resonance Spectrum (d ₆ -DMSO, ppm): 0.05 (s, CH ₃ ), 0.95 (t, J = 8Hz, -CH ₂ -), 4.13 (t, J = 8Hz, -CH ₂ -), 5.14 (dd, J = 5.8Hz, C ₃ H), 5.44 (d, J = 5Hz, C ₄ H), 6.70 (s, moiety XXV), 7 , 15-7.53 (m, aromatic H), 8.73 (s, NH) and 9.08 (d, J = 8Hz, NH).

EXAMPLE 103 250 ml of (3R, 4R) -4- (2-acetamidoethylthio) -3- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1 -methylethoxyimino) acetamido] -2-oxoazetidine-1-sulfonic acid and the vial was sealed under a pressure of 50 mm Hg to give a pharmaceutical.

Example 104 To a sterile vial of 500 ml is added 500 mg of (3R, 4R) -4-methylthio-3- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) ) -acetamido] -2-oxoazetidine-1-sulfonic acid and then the vial is sealed.

Example 705

Aseptically, 250 g of Cefotiam and 250 g of (3R, 4R) -4-methylthio-3- {2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) are mixed. ) -acetamido] -2-oxo-azetidine-1-sulfonic acid and 250-250 mg of the resulting mixture are weighed into 12 ml sterile vials. The vials were sealed at 50 mm Hg.

EXAMPLE 106 250 mg of (3R, 4R) -4-methylthio-3- [2- (2-aminothiazol-4-yl) -2-methoxyimino) acetamido] -2-oxo are added to a sterile vial. The azetidine-1-sulfonic acid sodium salt is sealed and the vial is sealed.

-521

189,545

EXAMPLE 107 500 ml of (3R, 4S) -4-phenylthio-3- [2- (2-aminothiazol-4-yl) -2-methoxyimino) acetamido] -2-oxo are weighed into a sterile vial. The azetidine-1-sulfonic acid sodium salt is sealed and the vial is sealed.

Claims (14)

Claims A process for the preparation of a 2-oxoazetidine derivative of formula (I): wherein: X is hydrogen or methoxy, R ₄ is (1) azido, (2) halo, (3) a group of formula (VIII) wherein R 1 is 1 cycloalkyl of 4 to 8 carbon atoms, 2 C 1 -C 6 alkyl optionally substituted by (a) an alkyl group containing 1 to 4 carbon atoms in the alkyl moiety or (b) an amino group optionally substituted by formyl, p-nitrobenzyloxycarbonyl or a C 1 -C 4 alkanoyl group in the alkyl moiety . Thiocarbonyl substituted with 3 C 1-4 alkylthio groups, 4 C 2 -C 4 alkenyl optionally substituted with C 1 -C 4 alkanoylamino in the alkyl moiety, 5 phenyl groups, 6 1- (C 1 -C 4) alkyl-1 H -tetrazolyl, or 7 in the alkyl moiety an alkanoyl group having 1-4 carbon atoms, and n is 0, 1 or 2, (4) a group of formula (VI1), in which R _s is 1 C 1-4 alkyl optionally substituted with C 1-4 alkoxycarbonyl in the alkyl moiety, or 2 optionally substituted phenyl substituted by 1 to 4 carbon atoms in the alkyl moiety, or (5) a group of formula X wherein R ₅ is benzothiazolyl and R 1 is (1) a group of formula XI wherein R _e is isoxazolyl optionally substituted with 2,6-dichlorophenyl or C 1 -C 4 alkyl, (2) a group of formula XII in which wherein R ₇ is 1 a group of Formula XIII [wherein R 'is a compound of formula (XXXV) wherein A' is alkyl of 1 to 4 carbon atoms or a cycloalkyl of 4 to 8 carbon atoms or a group of formula (XXXVI) in which: A is hydrogen or sulfo or thiophene-3-aldoimido; or 2 is a group of Formula XIV wherein R ₈ and R 7 'are independently hydrogen or C 1-4 alkyl, and alkyl is C 1-4 alkylcarbamoyl or sulfo; and R ₉ represents 1 C 1-4 alkyl optionally substituted with hydroxy, formyloxy or C 2-4 alkynyl or halogen, 2 phenyl groups, 3 thienyl groups, Or 4 benzothiophenyl groups 5-amino-thiazolyl group, (3) a (XVI) with a group of formula in which R _lo is (XVII), a group of formula and the latter formula R _{12 is} thiazolyl optionally substituted with amino, haloacetamido, sulfoamino, formamido, tritylamino or alkylthio (C 1-4) alkylcarboxamido, and R 1 is alkyl of 1 to 6 carbon atoms or -R ₁₄ R ₁₅ and in the latter of which R _{14 is C} 1 -C 6 alkylene and R _{1 S is} carboxyl, optionally tri (C 1 -C 4) alkyl- silyl substituted (C 1 -C 4) alkoxycarbonyl or tetrazolyl group, (4) a group of formula (XIX) wherein R _{17 is} halogen, (5) a group of formula (XX) in which R _{9 is} phenyl, phenoxy or thienyl, (6) 2 - {[2- (trityl-amino- or amino) -thiazol-4-yl] -carboxymethyl-iminoxy} -2-methyl-propionamido, ( 7) for the preparation of a benzyloxycarboxamido, p-nitrobenzyloxycarboxamido or 2- [tri (C 1 -C 4) alkylsilyl] ethoxycarboxamido group or an amino group (8), and their pharmaceutically acceptable salts, that a) sulfonating a compound of formula II, wherein X and R ₄ are as defined herein, and R ₂ is one of the acylated amino groups represented by numbers (1) to (7) above, or a salt or 1-silyl derivative thereof; and optionally, when R _{2 represents an} acylated amino group, removing the acyl group, or (b) compounds of formula (IV) which form a narrower group of compounds of formula (I) wherein X and R ₄ are as defined herein and R _{3 is one of} the acylated amino groups represented by numbers (1) to (7) above - preparation of (III) a compound of the formula: - wherein X and R ₄ are as defined above - is acylated with the above (1) - with an acylating agent containing numbered (7) are acylamino groups of any of acylating, if desired, a) or b) The compound of formula (I) prepared according to process A3 is converted into a pharmaceutically acceptable salt. (Priority: November 26, 1981) 2. A process according to claim 1 wherein the compounds of formula I are present -531 189,545 R ₄ is (1) azido, (2) a group of formula (VIII) wherein R ₅ is 1 cycloalkyl of 4 to 8 carbon atoms, 2 C 1-6 alkyl optionally substituted by (a) an alkyl group containing 1 to 4 carbon atoms in the alkyl moiety or (b) an amino group optionally substituted by formyl, p-nitrobenzyloxycarbonyl or an alkyl group containing 1 to 4 carbon atoms in the alkyl moiety. can be replaced, Thiocarbonyl substituted with 3 C 1-4 alkylthio groups, 4 C 2 -C 4 alkenyl optionally substituted by 1 to 4 carbon atoms in the alkyl moiety substituted by an alkanoylamino group, 5 phenyl groups, 6 1- (C 1 -C 4) alkyl-1 H -tetrazolyl, or 7 is an alkanoyl group having from 1 to 4 carbon atoms in the alkyl moiety and n is 0 or 1. (3) a group of formula (VII) wherein R is In this case, the alkyl moiety is substituted with 1 to 4 carbon atoms containing 1 to 4 carbon atoms in the alkyl moiety, or 2 optionally substituted with policy groups alkanoilesoport containing 1 to 4 carbon atoms in the alkyl part, or (4) a (X) group of the formula in which R _s is benzothiazolyl, and R ₂ and X are as defined in claim 1, characterized in that suitably substituted starting materials are used. (Priority: November 26, 1981) 3. A process according to claim 2 for the preparation of a compound of formula I wherein: R 1 is a group of formula XVI, wherein R ₁₀ is a group of formula XVII, and in the latter formula R _{12 is} thiazolyl optionally substituted with amino, haloacetamido, sulfoamino, formamido, tritylamino or alkylthio (C 1-4) alkylcarboxamide (C 1-4), and Haloalkyl containing 1 to 6 carbon atoms R ₁₃ R ₁₄ R ₁₅ group of formula and alkylene and R, R _{14 and} carboxyl containing 1 to 6 carbon atoms in the latter formula are optionally substituted with (C l -C 4) alkyl tri a silyl substituted (C 1-4) alkoxycarbonyl or tetrazolyl group, while R ₄ and X are as defined in claim 2, wherein appropriately substituted starting materials are used. (Priority: 1980. May 12) A process according to claim 3 for the preparation of compounds of formula I wherein R 1 is a group of formula XVII, wherein R ₂ is as defined in claim 3 and R ₁₃ is - R ₄ R 1 ₅ általá52 well group of the formula and the latter formula, R ₁₅ is carboxy or optionally tri (l-4 carbon atoms tartalmazójalkil-silyl-substituted alkoxycarbonyl (1-4C), and R _I4, or R ₄ and X have the third The use of appropriately substituted starting materials as claimed in Claim 1 to 5, (Preferred 12/12/1980). A process according to claim 2 for the preparation of compounds of formula (I) wherein X is hydrogen and R ₂ and R ₄ are as defined in claim 2, wherein the appropriately substituted starting materials are used. (Priority: December 12, 1980) 6. A process according to claim 2 for the preparation of 3- [2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -4-methylthio-2-oxoazetidine-1-sulfonic acid or a salt thereof. using appropriately substituted starting materials. (Priority: August 25, 1981) The process of claim 2, 3- [2- (2-Aminothiazol-4-yl) -2- (1-carboxy-1-methyl-ethoxyimino) -acetamido] -4-methylthio-2-oxo azetidine-1-sulfonic acid or a salt thereof, wherein the appropriately substituted starting material is used. (Priority: August 25, 1981) The process of claim 2, wherein 4- (2-acetamidoethylthio) -3- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxy) -imino) acetamido] -2-oxoazetidine-1-sulfonic acid or a salt thereof, characterized in that an appropriately substituted starting material is used. (Priority: November 26, 1981) The process according to claim 2, 4-azido-3- [2- (2-aminothiazol-4-yl) -2- (1-carboxy-1-methylethoxyimino) acetamido] -2-oxoazetidine- 1-sulfonic acid, characterized in that an appropriately substituted starting material is used. (Priority: November 26, 1981) A process according to claim 1 for the preparation of a compound of formula (I) wherein: X is hydrogen or methoxy, R ₄ is (1) azido, (2) halo, (3) a group of formula (VIII) wherein R ₅ is 1 cycloalkyl of 4 to 8 carbon atoms, 2 C 1 -C 6 alkyl optionally substituted by (a) an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety or (b) an amino group optionally substituted by formyl or alkanoyl group having 14 carbon atoms in the alkyl moiety, 3 C 2 -C 4 alkenyl optionally substituted with C 1 -C 4 alkanoylamino in the alkyl moiety, 4 phenyl groups, 5 1- (C 1 -C 4) alkyl-1 H -tetrazolyl, or 6 is an alkanoyl group having 1 to 4 carbon atoms in the alkyl moiety and n is 0, 1 or 2, -541 189,545. (4) a group of Formula VI1 wherein R 1 is 1 C 1-4 alkyl optionally substituted with C 1-4 alkoxycarbonyl in the alkyl moiety, or 2 is optionally substituted phenyl substituted with 1 to 4 carbon atoms in the alkyl moiety, or (5) a group of formula (X) wherein R 1 is benzothiazolyl, and R 1 is (1) a group of formula XI wherein R ₆ is isoxazolyl optionally substituted with 2,6-dichlorophenyl or C 1 -C 4 alkyl; (2) a group of formula XH wherein wherein R ₇ is 1 a group of Formula XIII [wherein R _g is a group of formula XXXV wherein A 'is C 1 -C 4 alkyl or C 4 -C 8 cycloalkyl or a compound of Formula XXXVI A is hydrogen or sulfo or thiophene-3-aldoimido; or 2 is a group of Formula XIV wherein R _B and R j are independently hydrogen or C 1-4 alkyl, and alkyl is C 1-4 alkylcarbamoyl or sulfo; and R 1 represents 1 C 1 -C 4 alkyl optionally substituted with halogen, 2 phenyl groups, 3 thienyl groups, Or 4 benzothiophenyl groups 5-amino-thiazolyl group, (3) a group (XVI), wherein, _{R] o} is (XVII), a group of formula and the latter formula R _{12 is} thiazolyl optionally substituted with amino, haloacetamido, sulfoamino, formamido, tritylamino or alkylthio (C 1-4) alkylcarboxamido, and R 3 is C 1 -C 6 alkyl or -R 14 R 15 and in the latter formula R _{4 is C} 1 -C 6 alkylene and R _{1 S is} carboxyl (C 1 -C 4) alkoxycarbonyl or tetrazolyl. (4) a group of formula (XIX) wherein R _{17 is} halogen; (5) a group of formula (XX) wherein R 1 is phenyl, phenoxy or thienyl; (6) benzyloxy; a carboxamido or p-nitrobenzyloxycarboxamido group, or an amino group (7), characterized in that appropriately substituted starting materials are used. (Priority: 30.4.1981) A process according to claim 10 for the preparation of a compound of formula (I) wherein: R ₄ is (1) an azido group, (2) formula (VIII) is a group of formula in which R _s is 1 cycloalkyl of 4 to 8 carbon atoms, 2 C 1-6 alkyl optionally substituted by (a) an alkyl group containing from 1 to 4 carbon atoms in the alkyl moiety or (b) an amino group substituted by formyl or an alkanoyl group containing from 1 to 4 carbon atoms in the alkyl moiety; 3 C 2 -C 4 alkenyl optionally substituted with C 1 -C 4 alkanoylamino in the alkyl moiety, 4 phenyl groups, 5 1- (C 1 -C 4) alkyl-1 H -tetrazolyl, or 6 is an alkanoyl group containing from 1 to 4 carbon atoms in the alkyl moiety, and n is 0, 1 or 2, (3) a group of formula VII wherein Rj is 1 C 1-4 alkyl optionally substituted with C 1-4 alkoxycarbonyl in the alkyl moiety, or 2 optionally substituted phenyl substituted with 1 to 4 carbon atoms in the alkyl moiety, or (4) a group of formula X wherein R 1 is benzothiazolyl and R and X are as defined in claim 10 wherein: suitably substituted starting materials are used. (Priority: December 12, 1980) 12. A process for the preparation of a pharmaceutical composition having an antimicrobial or β-lactamase inhibitory activity, characterized in that a compound of formula (I) according to claim 1, wherein the substituents are Or a pharmaceutically acceptable salt thereof as defined in claim 1 in admixture with excipients and / or excipients conventionally used in the manufacture of a pharmaceutical composition. (Priority: November 26, 1981) 13. A process for the preparation of a pharmaceutical composition having an antimicrobial or β-lactamase inhibitory activity, characterized in that a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 10, or a pharmaceutically acceptable salt thereof. in admixture with excipients and / or adjuvants commonly used in the pharmaceutical manufacture to form a pharmaceutical composition. (Priority: 30.4.1981) 14. A process for the preparation of a pharmaceutical composition having an antimicrobial or β-lactamase inhibitory activity, characterized in that a compound of any one of the invention. A compound of formula (I) as defined in claim 1, wherein the substituents are as defined in claim 11, or a pharmaceutically acceptable salt thereof, in admixture with excipients and / or excipients conventionally used in the manufacture of a medicament. (Priority: December 12, 1980)